Linear polyol stabilized polyfluoroacrylate compositions

ABSTRACT

The present invention is directed to compositions of a linear polyol and a salt of a crosslinked cation exchange polymer comprising a fluoro group and an acid group. These compositions are useful to bind potassium in the gastrointestinal tract.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/718,140 filed Dec. 18, 2012, which is a continuation of U.S. patentapplication Ser. No. 12/545,810, filed Aug. 22, 2009 (U.S. Pat. No.8,337,824), which is a non-provisional application of U.S. ProvisionalPatent Application Ser. No. 61/165,899, filed Apr. 1, 2009, and U.S.Provisional Patent Application Ser. No. 61/091,097, filed Aug. 22, 2008,the entirety of which are herein incorporated by reference.

FIELD OF THE INVENTION

The present invention is directed to compositions of a stabilizinglinear polyol and a salt of a crosslinked cation exchange polymercomprising a fluoro group and an acid group. These compositions areuseful to bind potassium in the gastrointestinal tract.

BACKGROUND OF THE INVENTION

Potassium (K⁺) is one of the most abundant intracellular cations.Potassium homeostasis is maintained predominantly through the regulationof renal excretion. Various medical conditions, such as decreased renalfunction, genitourinary disease, cancer, severe diabetes mellitus,congestive heart failure and/or the treatment of these conditions canlead to or predispose patients to hyperkalemia. Hyperkalemia can betreated with various cation exchange polymers includingpolyfluoroacrylic acid (polyFAA) as disclosed in WO 2005/097081.

Various polystyrene sulfonate cation exchange polymers (e.g.,Kayexalate®, Argamate®, Kionex®) have been used to treat hyperkalemia inpatients. These polymers and polymer compositions are known to havepatient compliance issues, including dosing size and frequency, tasteand/or texture, and gastric irritation. For example, in some patients,constipation develops, and sorbitol is thus commonly co-administered toavoid constipation, but this leads to diarrhea and othergastrointestinal side effects. It is also known that a wide variety ofsugars can be used in pharmaceutical compositions. See, for example, EP1785141.

Methods of reducing potassium and/or treatment of hyperkalemia have beenfound to raise patient compliance problems, in particular in chronicsettings, which are solved by the present invention. Such problemsinclude lack of tolerance of the therapeutically effective dose ofpolymeric binder (e.g., anorexia, nausea, gastric pain, vomiting andfecal impaction), dosing form (e.g., taste, mouth feel, etc.) and dosefrequency (e.g., three times per day). The present invention solvesthese problems by providing a polymeric binder or a compositioncontaining a polymeric binder that can be given once a day or twice aday without significant gastrointestinal side effects while retainingsubstantially similar efficacy. The methods of the present inventionreduce the frequency and form of administration of potassium binder andincrease tolerance, which will improve patient compliance, and potassiumbinding effectiveness.

It has been found that linear polyols in particular have a stabilizingeffect during storage on crosslinked poly alpha-fluoroacrylic acid inits salt form.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition thatcomprises a salt of a crosslinked cation exchange polymer and a linearpolyol stabilizer. Optionally, moisture is added to the composition. Thesalt of a preferred crosslinked cation exchange polymer is the productof the polymerization of at least two, and optionally three, differentmonomer units and is stabilized with respect to fluoride release. Amongthe various aspects of the invention is a composition comprising alinear polyol and a salt of a crosslinked cation exchange polymercomprising a fluoro group and an acid group that is the product of thepolymerization of at least two, and optionally three, different monomerunits. Typically, one monomer comprises a fluoro group and an acid groupand the other monomer is a difunctional arylene monomer or adifunctional alkylene, ether- or amide-containing monomer, or acombination thereof.

A further aspect of the invention is a pharmaceutical compositioncomprising a crosslinked cation exchange polymer salt and from about 10wt. % to about 40 wt. % of a linear polyol based on the total weight ofthe composition. The crosslinked cation exchange polymer comprisesstructural units corresponding to Formulae 1 and 2, Formulae 1 and 3, orFormulae 1, 2, and 3, wherein Formula 1, Formula 2, and Formula 3 arerepresented by the following structures:

wherein R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, oraryl; A₁ is carboxylic, phosphonic, or phosphoric; X₁ is arylene; and X₂is alkylene, an ether moiety, or an amide moiety. In some instances,Formula 1, Formula 2, and Formula 3 are represented by the followingstructures:

Another aspect of the invention is a pharmaceutical compositioncomprising a crosslinked cation exchange polymer salt and an effectiveamount of a linear polyol sufficient to stabilize the polymer salt,wherein the salt of the crosslinked cation exchange polymer comprisesstructural units corresponding to Formulae 1 and 2, Formulae 1 and 3, orFormulae 1, 2, and 3. In some instances, the structural units of Formula1, Formula 2 and Formula 3 correspond to Formula 1A, Formula 2A, andFormula 3A, respectively. Optionally, the composition further comprisesmoisture.

A further aspect is a pharmaceutical composition comprising acrosslinked cation exchange polymer salt and from about 10 wt. % toabout 40 wt. % of a linear polyol based on the total weight of thecomposition, the crosslinked cation exchange polymer being a reactionproduct of a polymerization mixture comprising monomers of either (i)Formulae 11 and 22, (ii) Formulae 11 and 33, or (iii) Formulae 11, 22,and 33. Formula 11, Formula 22, and Formula 33 are represented by thefollowing structures:

wherein R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, oraryl; A₁₁ is an optionally protected carboxylic, phosphonic, orphosphoric; X₁ is arylene; and X₂ is alkylene, an ether moiety, or anamide moiety. In some instances, Formula 11, Formula 22, and Formula 33are represented by the following structures:

Another aspect of the invention is a pharmaceutical compositioncomprising a crosslinked cation exchange polymer salt and an effectiveamount of a linear polyol sufficient to stabilize the polymer salt,wherein the salt of the crosslinked cation exchange polymer is areaction product of a polymerization mixture comprising monomerscorresponding to Formulae 11 and 22, Formulae 11 and 33, or Formulae 11,22, and 33. In some instances, Formula 1, Formula 2 and Formula 3correspond to Formula 11A, Formula 22A, and Formula 33A, respectively.Optionally the composition further comprises moisture.

Yet another aspect is a method for removing potassium from thegastrointestinal tract of an animal subject in need thereof. The methodcomprises administering any one of the crosslinked cation exchangepolymers or pharmaceutical compositions described herein to the subject,whereby the polymer or pharmaceutical composition passes through thegastrointestinal tract of the subject, and removes a therapeuticallyeffective amount of potassium ion from the gastrointestinal tract of thesubject. In some embodiments, the subject is a mammal, and preferably, ahuman.

A further aspect is a method for removing potassium from thegastrointestinal tract of an animal subject in need thereof, comprisingadministering an effective amount once per day or twice per day to thesubject of a crosslinked cation exchange polymer or any pharmaceuticalcomposition described herein, wherein the polymer comprises structuralunits corresponding to Formulae 1 and 2, Formulae 1 and 3, or Formulae1, 2, and 3, wherein Formula 1, Formula 2, and Formula 3 are representedby the following structures:

wherein R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, oraryl; A₁ is carboxylic, phosphonic, or phosphoric; X₁ is arylene; and X₂is alkylene, an ether moiety, or an amide moiety, wherein a daily amountof the polymer or composition has a potassium binding capacity of atleast 75% of the binding capacity of the same polymer or compositionadministered at the same daily amount three times per day.

The present invention also provides a method of removing potassium in ananimal subject in need thereof, comprising administering an effectiveamount once per day or twice per day to the subject of a crosslinkedcation exchange polymer or any pharmaceutical composition describedherein, wherein the polymer is the reaction product of a polymerizationmixture comprising monomers of either (i) Formulae 11 and 22, (ii)Formulae 11 and 33, or (iii) Formulae 11, 22, and 33. Formula 11,Formula 22, and Formula 33 are represented by the following structures:

wherein R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, oraryl; A₁₁ is an optionally protected carboxylic, phosphonic, orphosphoric; X₁ is arylene; and X₂ is alkylene, an ether moiety, or anamide moiety, wherein a daily amount of the polymer or the compositionhas a potassium binding capacity of at least 75% of the binding capacityof the same polymer or composition administered at the same daily amountthree times per day.

In other embodiments, the present invention provides a method ofremoving potassium from the gastrointestinal tract of an animal subjectin need thereof, comprising administering an effective amount once perday or twice per day to the subject of a daily amount of a crosslinkedcation exchange polymer or a pharmaceutical composition as describedherein, wherein either (1) less than 25% of subjects taking the polymeror composition once per day or twice per day experience mild or moderategastrointestinal adverse events or (2) a daily amount of the polymer orcomposition has a potassium binding capacity of at least 75% of the samedaily amount of the same polymer administered three times per day or (3)both.

It has also been found that use of a composition comprising acrosslinked aliphatic carboxylic polymer and an effective amount of, orin some instances from about 10 wt. % to about 40 wt. % of, a linearpolyol has increased efficacy for removal of potassium as compared to acomposition not containing the linear polyol. In this regard, increasedefficacy is measured by the amount of fecal excretion of potassium. Thecompositions and/or methods of this invention include a compositioncomprising an effective amount, or in some instances from about 10 wt. %to about 40 wt. %, of a linear polyol, and a crosslinked aliphaticcarboxylic polymer that extracts from an animal subject in need thereofabout 5% more potassium as compared to the same dose and sameadministration frequency of the same polymer without stabilization by alinear polyol.

DETAILED DESCRIPTION

The present invention is directed to pharmaceutical compositionscomprising a polyol and a salt of a crosslinked cation exchange polymer,with the polyol present in an amount sufficient to reduce the release offluoride ion from the cation exchange polymer during storage. In someembodiments, the pharmaceutical compositions of this inventionadditionally comprise water also present in an amount sufficient toreduce or assist in the reduction of the release of fluoride ion fromthe cation exchange polymer during storage. Generally, the salt of acrosslinked cation exchange polymer comprised a fluoro group and an acidgroup is the product of the polymerization of at least two, andoptionally three, different monomer units. Typically, one monomercomprises a fluoro group and an acid group and the other monomer is adifunctional arylene monomer or a difunctional alkylene, ether- oramide-containing monomer, or a combination thereof. These pharmaceuticalcompositions are useful to bind potassium in the gastrointestinal tract.In preferred embodiments, the linear polyol is a linear sugar alcohol.Increased efficacy, and/or tolerability in different dosing regimens, isseen as compared to compositions without the linear polyol, andoptionally including water.

A linear polyol is added to the composition containing the salt of acrosslinked cation exchange polymer in an amount effective to stabilizethe polymer salt, and generally from about 10 wt. % to about 40 wt. %linear polyol based on the total weight of the composition. The linearpolyol is preferably a linear sugar (i.e, a linear sugar alcohol). Thelinear sugar alcohol is preferably selected from the group consisting ofD-(+)arabitol, erythritol, glycerol, maltitol, D-mannitol, ribitol,D-sorbitol, xylitol, threitol, galactitol, isomalt, iditol, lactitol andcombinations thereof, more preferably selected from the group consistingof D-(+)arabitol, erythritol, glycerol, maltitol, D-mannitol, ribitol,D-sorbitol, xylitol, and combinations thereof, and most preferablyselected from the group consisting of xylitol, sorbitol, and acombination thereof. Preferably, the pharmaceutical composition containsfrom about 15 wt. % to about 35 wt. % stabilizing polyol based on thetotal weight of the composition. In various embodiments, this linearpolyol concentration is sufficient to reduce the release of fluoride ionfrom the cation exchange polymer upon storage as compared to anotherwise identical composition containing no stabilizing polyol at thesame temperature and storage time.

The moisture content of the composition can be balanced with thestabilizing linear polyol to provide a stabilized polymer within thecomposition. In general, as the moisture content of the compositionincreases, the concentration of polyol can be decreased. However, themoisture content should not rise so high as to prevent the compositionfrom being free flowing during manufacturing or packaging operations. Ingeneral, the moisture content can range from about 1 to about 30 weightpercent based on the total weight of the composition. More specifically,the moisture content can be from about 10 to about 25 wt. % based on thetotal weight of the composition of polymer, linear polyol and water. Inone specific case, the pharmaceutical composition comprises about 10-40wt. % linear polyol, about 1-30 wt. % water and the remaindercrosslinked cation exchange polymer, with the weight percents based onthe total weight of linear polyol, water and polymer. Also, in aspecific case, the pharmaceutical composition comprises about 15 wt. %to about 35 wt. % linear polyol, about 10 wt. % to about 25 wt % waterand the remainder crosslinked cation exchange polymer, with the weightpercents based on the total weight of linear polyol, water and polymer.In another specific case, the pharmaceutical composition comprises fromabout 10 wt. % to about 40 wt. % linear polyol and the remaindercrosslinked cation exchange polymer, with the weight percents based onthe total weight of linear polyol and polymer.

The moisture content can be measured in a manner known to those of skillin the art. Moisture content in the composition may be determined by twomethods: (a) thermogravimetric method via a moisture analyzer duringin-process manufacturing or (b) measuring loss on drying in accordancewith US Pharmacopeia (USP) <731>. The operating condition for thethermogravimetric method via moisture analyzer is 0.3 g of polymercomposition heated at about 160° C. for about 45 min. The operatingcondition for the USP <731> method is 1.5-2 g of polymer compositionheated to about 130° C. for about 16 hours under 25-35 mbar vacuum.

From a stabilizing viewpoint, the concentration of inorganic fluoride(e.g., from fluoride ion) in the pharmaceutical composition is less thanabout 1000 ppm, less than about 500 ppm or less than about 300 ppm undertypical storage conditions. More particularly, the concentration ofinorganic fluoride in the pharmaceutical composition is less than about1000 ppm after storage at accelerated storage conditions (about 40° C.for about 6 weeks), less than about 500 ppm after room temperaturestorage (about 25° C. for about 6 weeks), or less than about 300 ppmafter refrigerated storage (about 5° C. for about 6 weeks).Additionally, the concentration of inorganic fluoride in thepharmaceutical composition is generally 50% less and preferably 75% lessthan the concentration of inorganic fluoride in the otherwise identicalcomposition containing no stabilizing polyol at the same temperature andstorage time.

The pharmaceutical composition comprises a crosslinked carboxylic cationexchange polymer. Specifically, the composition includes a crosslinkedcation exchange polymer comprising structural units corresponding toFormulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3, whereinFormula 1, Formula 2, and Formula 3 are represented by the followingstructures:

wherein R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, oraryl; A₁ is carboxylic, phosphonic, or phosphoric; X₁ is arylene; and X₂is alkylene, an ether moiety, or an amide moiety. More specifically, R₁and R₂ are each independently hydrogen, alkyl, cycloalkyl, or aryl; A₁is carboxylic, phosphonic, or phosphoric; X₁ is arylene; and X₂ isalkylene, an ether moiety, or an amide moiety.

When X₂ is an ether moiety, the ether moiety can be—(CH₂)_(d)—O—(CH₂)_(e)— or —(CH₂)_(d)—O—(CH₂)_(e)—(CH₂)_(d)—, wherein dand e are independently an integer of 1 through 5. In some instances, dis an integer from 1 to 2 and e is an integer from 1 to 3. When X₂ is anamide moiety, the amide moiety can be —C(O)—NH—(CH₂)_(p)—NH—C(O)—wherein p is an integer of 1 through 8. In some instances, p is aninteger of 4 to 6.

The unit corresponding to Formula 2 can be derived from a difunctionalcrosslinking monomer having the formula CH₂═CH—X₁—CH═CH₂ wherein X₁ isas defined in connection with Formula 2. Further, the unit correspondingto Formula 3 can be derived from a difunctional crosslinking monomerhaving the formula CH₂═CH—X₂—CH═CH₂ wherein X₂ is as defined inconnection with Formula 3.

In connection with Formula 1, in one embodiment, R₁ and R₂ are hydrogenand A₁ is carboxylic. In connection with Formula 2, in one embodiment,X₁ is an optionally substituted phenylene, and preferably phenylene. Inconnection with Formula 3, in one embodiment, X₂ is optionallysubstituted ethylene, propylene, butylene, pentylene, or hexylene; morespecifically, X₂ is ethylene, propylene, butylene, pentylene, orhexylene; and preferably X₂ is butylene. In one specific embodiment, R₁and R₂ are hydrogen, A₁ is carboxylic, X₁ is phenylene and X₂ isbutylene.

In one embodiment, the crosslinked cation exchange polymer comprises atleast about 80 wt. %, particularly at least about 85 wt. %, and moreparticularly at least about 90 wt. % or from about 80 wt. % to about 95wt. %, from about 85 wt. % to about 95 wt. %, from about 85 wt. % toabout 93 wt. % or from about 88 wt. % to about 92 wt. % of structuralunits corresponding to Formula 1 based on the total weight of thestructural units as used in the polymerization mixture corresponding to(i) Formulae 1 and 2, (ii) Formulae 1 and 3, or (iii) Formulae 1, 2, and3. Additionally, the polymer can comprise a unit of Formula 1 having amole fraction of at least about 0.87 or from about 0.87 to about 0.94 orfrom about 0.90 to about 0.92 based on the total number of moles of theunits corresponding to (i) Formulae 1 and 2, (ii) Formulae 1 and 3, or(iii) Formulae 1, 2, and 3.

In one embodiment, the polymer contains structural units of Formulae 1,2, and 3 and has a weight ratio of the structural unit corresponding toFormula 2 to the structural unit corresponding to Formula 3 of fromabout 4:1 to about 1:4, from about 2:1 to 1:2, or about 1:1.Additionally, this polymer can have a mole ratio of the structural unitof Formula 2 to the structural unit of Formula 3 of from about 0.2:1 toabout 7:1, from about 0.2:1 to about 3.5:1; from about 0.5:1 to about1.3:1, from about 0.8 to about 0.9, or about 0.85:1.

Generally, the Formulae 1, 2 and 3 structural units of the terpolymerhave specific ratios, for example, wherein the structural unitscorresponding to Formula 1 constitute at least about 85 wt. % or fromabout 80 to about 95 wt. %, from about 85 wt. % to about 93 wt. %, orfrom about 88 wt. % to about 92 wt. % based on the total weight ofstructural units of Formulae 1, 2, and 3 in the polymer, calculatedbased on the amounts of monomers of Formulae 11, 22, and 33 used in thepolymerization reaction, and the weight ratio of the structural unitcorresponding to Formula 2 to the structural unit corresponding toFormula 3 is from about 4:1 to about 1:4, or about 1:1. Further, theratio of structural units when expressed as the mole fraction of thestructural unit of Formula 1 in the polymer is at least about 0.87 orfrom about 0.87 to about 0.94, or from about 0.9 to about 0.92, based onthe total number of moles of the structural units of Formulae 1, 2, and3, and the mole ratio of the structural unit of Formula 2 to thestructural unit of Formula 3 is from about 0.2:1 to about 7:1, fromabout 0.2:1 to about 3.5:1, or from about 0.8 to about 0.9; or 0.85:1;again these calculations are performed using the amounts of monomers ofFormulae 11, 22, and 33 used in the polymerization reaction. It is notnecessary to calculate conversion.

In some aspects, the crosslinked cation exchange polymer comprises unitscorresponding to (i) Formulae 1A and 2A, (ii) Formulae 1A and 3A, or(iii) Formulae 1A, 2A, and 3A, wherein Formulae 1A, 2A and 3A aregenerally represented by the following structures.

In Formula 1 or 1A, the carboxylic acid is preferably in the salt form(i.e., balanced with a counter-ion such as Ca²⁺, Mg²⁺, Na⁻, NH⁴⁺, andthe like). Preferably, the carboxylic acid is in the salt form andbalanced with a Ca²⁺ counterion. When the carboxylic acid of thecrosslinked cation exchange form is balanced with a divalent counterion,two carboxylic acid groups can be associated with the one divalentcation.

The structural units of the terpolymer can have specific ratios, forexample, wherein the structural units corresponding to Formula 1Aconstitute at least about 85 wt. % or from about 80 to about 95 wt. %,from about 85 wt. % to about 93 wt. %, or from about 88 wt. % to about92 wt. % based on the total weight of structural units of Formulae 1A,2A, and 3A, calculated based on the amounts of monomers of Formulae 11A,22A, and 33A used in the polymerization reaction, and the weight ratioof the structural unit corresponding to Formula 2A to the structuralunit corresponding to Formula 3A is from about 4:1 to about 1:4, orabout 1:1. Further, the ratio of structural units when expressed as themole fraction of the structural unit of Formula 1A in the polymer is atleast about 0.87 or from about 0.87 to about 0.94, or from about 0.9 toabout 0.92 based on the total number of moles of the structural units ofFormulae 1A, 2A, and 3A calculated from the amount of monomers ofFormulae 11A, 22A, and 33A used in the polymerization reaction, and themole ratio of the structural unit of Formula 2A to the structural unitof Formula 3A is from about 0.2:1 to about 7:1, from about 0.2:1 toabout 3.5:1, from about 0.5:1 to about 1.3:1, from about 0.8:1 to about0.9:1, or about 0.85:1.

The polymers described herein are generally random polymers wherein theexact order of the structural units of Formulae 1, 2, or 3 (derived frommonomers of Formulae 11, 22, or 33), or 1A, 2A, or 3A (derived frommonomers of Formulae 11A, 22A, or 33A) is not predetermined.

A cation exchange polymer derived from monomers of Formulae 11, 22, and33, followed by hydrolysis, can have a structure represented as follows:

wherein R₁, R₂, A₁, X₁, and X₂ are as defined in connection withFormulae 1, 2, and 3 and m is in the range of from about 85 to about 93mol %, n is in the range of from about 1 to about 10 mol % and p is inthe range of from about 1 to about 10 mol %, calculated based on theratios of monomers added to the polymerization mixture. The wavy bondsin the polymer structures of Formula 40 are included to represent therandom attachment of structural units to one another wherein thestructural unit of Formula 1 can be attached to another structural unitof Formula 1, a structural unit of Formula 2, or a structural unit ofFormula 3; the structural units of Formulae 2 and 3 have the same rangeof attachment possibilities.

Using the polymerization process described herein, with monomersgenerally represented by Formulae 11A, 22A and 33A, followed byhydrolysis and calcium ion exchange, a polymer represented by thegeneral structure shown below is obtained:

wherein m is in the range of from about 85 to about 93 mol %, n is inthe range of from about 1 to about 10 mol % and p is in the range offrom about 1 to about 10 mol %, calculated based on the ratios ofmonomers added to the polymerization mixture. The wavy bonds in thepolymer structures of Formula 40A are included to represent the randomattachment of structural units to one another wherein the structuralunit of Formula 1A can be attached to another structural unit of Formula1A, a structural unit of Formula 2A, or a structural unit of Formula 3A;the structural units of Formulae 2A and 3A have the same range ofattachment possibilities.

The crosslinked cation exchange polymer is generally the reactionproduct of a polymerization mixture that is subjected to polymerizationconditions. The polymerization mixture may also contain components thatare not chemically incorporated into the polymer. The crosslinked cationexchange polymer typically comprises a fluoro group and an acid groupthat is the product of the polymerization of at least two, andoptionally three, different monomer units where one monomer comprises afluoro group and an acid group and the other monomer is a difunctionalarylene monomer or a difunctional alkylene, ether- or amide-containingmonomer, or a combination thereof. More specifically, the crosslinkedcation exchange polymer can be a reaction product of a polymerizationmixture comprising monomers of (i) Formulae 11 and 22, (ii) Formulae 11and 33, or (iii) Formulae 11, 22, and 33. The monomers of Formulae 11,22, and 33 are generally represented by

wherein R₁ and R₂ are as defined in connection with Formula 1, X₁ is asdefined in connection with Formula 2, X₂ is as defined in connectionwith Formula 3, and A₁₁ is an optionally protected carboxylic,phosphonic, or phosphoric. In a preferred embodiment, A₁₁ is a protectedcarboxylic, phosphonic, or phosphoric. The product of a polymerizationreaction comprising monomers of (i) Formulae 11 and 22, (ii) Formulae 11and 33, or (iii) Formulae 11, 22, and 33 comprises a polymer havingoptionally protected acid groups and comprising units corresponding toFormula 10 and units corresponding to Formulae 2 and 3. Polymer productshaving protected acid groups can be hydrolyzed to form a polymer havingunprotected acid groups and comprising units corresponding to Formulae1, 2, and 3. The structural units generally represented by Formula 10have the structure

wherein R₁, R₂, and A₁₁ are as defined in connection with Formula 11.

In preferred embodiments of any of the methods of the invention whereinthe crosslinked cation exchange polymer is a reaction product of apolymerization mixture of monomers, A11 is a protected carboxylic,phosphonic, or phosphoric. The polymer formed in the polymerizationreaction contains protected carboxylic, phosphonic, or phosphoricgroups. A hydrolysis agent can be added to the polymer formed in thepolymerization reaction to hydrolyze these protected groups, convertingthem to carboxylic, phosphonic, or phosphoric groups, or other methodsof deprotection well known in the art can be used. The hydrolyzedpolymer is preferably subjected to ion exchange to obtain a preferredpolymer salt for therapeutic use.

In one embodiment, the reaction mixture comprises at least about 80 wt.%, particularly at least about 85 wt. %, and more particularly at leastabout 90 wt. % or from about 80 wt. % to about 95 wt. %, from about 85wt. % to about 95 wt. %, from about 85 wt. % to about 93 wt. % or fromabout 88 wt. % to about 92 wt. % of monomers corresponding to Formula 11based on the total weight of the monomers corresponding to (i) Formulae11 and 22, (ii) Formulae 11 and 33, or (iii) Formulae 11, 22, and 33.Additionally, the reaction mixture can comprise a unit of Formula 11having a mole fraction of at least about 0.87 or from about 0.87 toabout 0.94 based on the total number of moles of the monomerscorresponding to (i) Formulae 11 and 22, (ii) Formulae 11 and 33, or(iii) Formulae 11, 22, and 33.

In one embodiment, the polymerization reaction mixture contains monomersof Formulae 11, 22, and 33 and has a weight ratio of the monomercorresponding to Formula 22 to the monomer corresponding to Formula 33from about 4:1 to about 1:4, from about 2:1 to 1:2, or about 1:1.Additionally, this mixture can have a mole ratio of the monomer ofFormula 22 to the monomer of Formula 33 from about 0.2:1 to about 7:1,from 0.2:1 to 3.5:1, from about 0.5:1 to about 1.3:1, from about 0.8:1to about 0.9:1, or about 0.85:1.

Particular crosslinked cation exchange polymers are the reaction productof a polymerization mixture comprising monomers of (i) Formulae 11 and22, (ii) Formulae 11 and 33, or (iii) Formulae 11, 22, and 33. Themonomers are generally represented by Formulae 11A, 22A, and 33A havingthe structure:

wherein alkyl is preferably selected from methyl, ethyl, propyl,iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl,sec-pentyl, or tert-pentyl. Most preferably, the alkyl group is methylor tert-butyl. The —O-alkyl moiety protects the carboxyl moiety fromreacting with other reactive moieties during the polymerization reactionand can be removed by hydrolysis or other deprotection methods asdescribed in more detail below.

Further, the polymerization reaction mixture contains at least about 80wt. %, particularly at least about 85 wt. %, and more particularly atleast about 90 wt. % or from about 80 wt. % to about 95 wt. %, fromabout 85 wt. % to about 95 wt. %, from about 85 wt. % to about 93 wt. %or from about 88 wt. % to about 92 wt. % of monomers corresponding toFormula 11A based on the total weight of the monomers which aregenerally represented by (i) Formulae 11A and 22A, (ii) Formulae 11A and33A, or (iii) Formulae 11A, 22A, and 33A. Additionally, the reactionmixture can comprise a unit of Formula 11A having a mole fraction of atleast about 0.87 or from about 0.87 to about 0.94 or from about 0.9 toabout 0.92 based on the total number of moles of the monomers present inthe polymer which are generally represented by (i) Formulae 11A and 22A,(ii) Formulae 11A and 33A, or (iii) Formulae 11A, 22A, and 33A.

In some instances, the reaction mixture contains monomers of Formulae11, 22, and 33 and the weight ratio of the monomer generally representedby Formula 22A to the monomer generally represented by Formula 33A offrom about 4:1 to about 1:4 or about 1:1. Also, this mixture has a moleratio of the monomer of Formula 22A to the monomer of Formula 33A offrom about 0.2:1 to about 7:1, from about 0.2:1 to about 3.5:1, fromabout 0.5:1 to about 1.3:1, from about 0.8:1 to about 0.9:1, or about0.85:1.

In a preferred embodiment, an initiated polymerization reaction isemployed where a polymerization initiator is used in the polymerizationreaction mixture to aid initiation of the polymerization reaction. Whenpreparing poly(methylfluoroacrylate) or (polyMeFA) or any othercrosslinked cation exchange polymer used in the invention in asuspension polymerization reaction, the nature of the free radicalinitiator plays a role in the quality of the suspension in terms ofpolymer particle stability, yield of polymer particles, and the polymerparticle shape. Use of water-insoluble free radical initiators, such aslauroyl peroxide, can produce polymer particles in a high yield. Withoutbeing bound by any particular theory, it is believed that awater-insoluble free radical initiator initiates polymerizationprimarily within the dispersed phase containing the monomers of Formulae11 and 22, 11 and 33, or 11, 22, and 33. Such a reaction scheme providespolymer particles rather than a bulk polymer gel. Thus, the process usesfree radical initiators with water solubility lower than 0.1 g/L,particularly lower than 0.01 g/L. In particular embodiments,polymethylfluoroacrylate particles are produced with a combination of alow water solubility free radical initiator and the presence of a saltin the aqueous phase, such as sodium chloride.

The polymerization initiator can be chosen from a variety of classes ofinitiators. For instance, initiators that generate polymer imitatingradicals upon exposure to heat include peroxides, persulfates or azotype initiators (e.g., 2,2′-azobis(2-methylpropionitrile), lauroylperoxide (LPO), tert-butyl hydro peroxide,dimethyl-2,2′-azobis(2-methylpropionate),2,2′-azobis(2-methyl-N-(2-hydroxyethyl)propionamide),2,2′-azobis(2-(2-imidazolin-2-yl)propane), (2,2″-azobis(2,4-dimethylvaleronitrile), azobisisobutyronitrile (AIBN) or acombination thereof. Another class of polymer initiating radicals isradicals generated from redox reactions, such as persulfates and amines.Radicals can also be generated by exposing certain initiators to UVlight or exposure to air.

For those polymerization reactions that contain additional components inthe polymerization mixture that are not intended to be incorporated intothe polymer, such additional components typically comprise surfactants,solvents, salts, buffers, aqueous phase polymerization inhibitors and/orother components known to those of skill in the art. When thepolymerization is carried out in a suspension mode, the additionalcomponents may be contained in an aqueous phase while the monomers andinitiator may be contained in an organic phase. When an aqueous phase ispresent, the aqueous phase may be comprised of water, surfactants,stabilizers, buffers, salts, and polymerization inhibitors. A surfactantmay be selected from the group consisting of anionic, cationic,nonionic, amphoteric, zwitterionic, or a combination thereof. Anionicsurfactants are typically based on sulfate, sulfonate or carboxylateanions. These surfactants include, sodium dodecyl sulfate (SDS),ammonium lauryl sulfate, other alkyl sulfate salts, sodium laurethsulfate (or sodium lauryl ether sulfate (SLES)), N-lauroylsarcosinesodium salt, lauryldimethylamine-oxide (LDAO),ethyltrimethylammoniumbromide (CTAB), bis(2-ethylhexyl)sulfosuccinatesodium salt, alkyl benzene sulfonate, soaps, fatty acid salts, or acombination thereof. Cationic surfactants, for example, containquaternary ammonium cations. These surfactants are cetyltrimethylammonium bromide (CTAB or hexadecyl trimethyl ammoniumbromide), cetylpyridinium chloride (CPC), polyethoxylated tallow amine(POEA), benzalkonium chloride (BAC), benzethonium chloride (BZT), or acombination thereof. Zwitterionic or amphoteric surfactants includedodecyl betaine, dodecyl dimethylamine oxide, cocamidopropyl betaine,coco ampho glycinate, or a combination thereof. Nonionic surfactantsinclude alkyl poly(ethylene oxide), copolymers of poly(ethylene oxide)and poly(propylene oxide) (commercially called Poloxamers orPoloxamines), alkyl polyglucosides (including octyl glucoside, decylmaltoside, fatty alcohols, cetyl alcohol, oleyl alcohol, cocamide MEA,cocamide DEA), or a combination thereof. Other pharmaceuticallyacceptable surfactants are well known in the art and are described inMcCutcheon's Emulsifiers and Detergents, N. American Edition (2007).

Polymerization reaction stabilizers may be selected from the groupconsisting of organic polymers and inorganic particulate stabilizers.Examples include polyvinyl alcohol-co-vinylacetate and its range ofhydrolyzed products, polyvinylacetate, polyvinylpyrolidinone, salts ofpolyacrylic acid, cellulose ethers, natural gums, or a combinationthereof.

Buffers may be selected from the group consisting of for example,4-2-hydroxyethyl-1-piperazineethanesulfonic acid,2-{[tris(hydroxymethyl)methyl]amino}ethanesulfonic acid,3-(N-morpholino)propanesulfonic acid,piperazine-N,N′-bis(2-ethanesulfonic acid), sodium phosphate dibasicheptahydrate, sodium phosphate monobasic monohydrate or a combinationthereof.

Polymerization reaction salts may be selected from the group consistingof potassium chloride, calcium chloride, potassium bromide, sodiumbromide, sodium bicarbonate, ammonium peroxodisulfate, or a combinationthereof.

Polymerization inhibitors may be used as known in the art and selectedfrom the group consisting of1,1,3-tris(2-methyl-4-hydroxy-5-tert-butylphenyl)butane,1,3,5-trimethyl-2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)benzene,1-aza-3,7-dioxabicyclo[3.3.0]octane-5-methanol,2,2′-ethylidene-bis(4,6-di-tert-butylphenol),2,2′-ethylidenebis(4,6-di-tert-butylphenyl) fluorophosphite,2,2′-methylenebis(6-tert-butyl-4-ethylphenol),2,2′-methylenebis(6-tert-butyl-4-methylphenol),2,5-di-tert-butyl-4-methoxyphenol,2,6-di-tert-butyl-4-(dimethylaminomethyl)phenol, 2-heptanone oxime,3,3′,5,5′-tetramethylbiphenyl-4,4′-diol,3,9-bis(2,4-dicumylphenoxy)-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane,4,4-dimethyloxazolidine, 4-methyl-2-pentanone oxime,5-ethyl-1-aza-3,7-dioxabicyclo[3.3.0]octane,6,6′-dihydroxy-5,5′-dimethoxy-[1,1′-biphenyl]-3,3′-dicarboxaldehyde,distearyl-3,3′-thiodipropionate, ditetradecyl-3,3′-thiodipropionate,ditridecyl-3,3′-thiodipropionate,octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate,pentaerythritol tetrakis(3,5-di-tert-butyl-4-hydroxyhydrocinnamate),poly(1,2-dihydro-2,2,4-trimethylquinoline), sodium D-isoascorbatemonohydrate,tetrakis(2,4-di-tert-butylphenyl)-4,4′-biphenyldiphosphonite,tris(3,5-di-tert-butyl-4-hydroxybenzyl) isocyanurate,tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl) isocyanurate, sodiumnitrite or a combination thereof.

Generally, the polymerization mixture is subjected to polymerizationconditions. While suspension polymerization is preferred, as alreadydiscussed herein, the polymers used in this invention may also beprepared in bulk, solution or emulsion polymerization processes. Thedetails of such processes are within the skill of one of ordinary skillin the art based on the disclosure of this invention. The polymerizationconditions typically include polymerization reaction temperatures,pressures, mixing and reactor geometry, sequence and rate of addition ofpolymerization mixtures and the like. Polymerization temperatures aretypically in the range of from about 50 to 100° C. Polymerizationpressures are typically run at atmospheric pressure, but can be run athigher pressures (for example 130 PSI of nitrogen). Polymerizationmixing depends on the scale of the polymerization and the equipmentused, and is within the skill of one of ordinary skill in the art.Various alpha-fluoroacrylate polymers and the synthesis of thesepolymers are described in U.S. Patent Application Publication No.2005/0220752, herein incorporated by reference.

As described in more detail in connection with the examples herein, invarious particular embodiments, the crosslinked cation exchange polymercan be synthesized by preparing an organic phase and an aqueous phase.The organic phase typically contains a polymerization initiator and (i)a monomer of Formula 11 and a monomer of Formula 22, (ii) a monomer ofFormula 11 and a monomer of Formula 33, or (iii) monomers of Formulae11, 22, and 33. The aqueous phase generally contains a polymerizationsuspension stabilizer, a water soluble salt, water, and optionally abuffer. The organic phase and the aqueous phase are then combined andstirred under nitrogen. The mixture is generally heated to about 60° C.to about 80° C. for about 2.5 to about 3.5 hours, allowed to rise up to95° C. after polymerization is initiated, and then cooled to roomtemperature. After cooling, the aqueous phase is removed. Water is addedto the mixture, the mixture is stirred, and the resulting solid isfiltered. The solid is washed with water, alcohol, or alcohol/watermixtures.

As described above, polymerization suspension stabilizers, such aspolyvinyl alcohol, are used to prevent coalescence of particles duringthe polymerization process. Further, it has been observed that theaddition of sodium chloride in the aqueous phase decreased coalescenceand particle aggregation. Other suitable salts for this purpose includesalts that are soluble in the aqueous phase. In this embodiment, watersoluble salts are added at a concentration of from about 0.1 wt. % toabout 10 wt. %, particularly from about 2 wt. % to about 5 wt. %, andeven more particularly from about 3 wt. % to about 4 wt. %.

Preferably, an organic phase of methyl 2-fluoroacrylate (90 wt. %),1,7-octadiene (5 wt. %) and divinylbenzene (5 wt. %) is prepared and 0.5wt. % of lauroyl peroxide is added to initiate the polymerizationreaction. Additionally, an aqueous phase of water, polyvinyl alcohol,phosphates, sodium chloride, and sodium nitrite is prepared. Undernitrogen and while keeping the temperature below about 30° C., theaqueous and organic phases are mixed together. Once mixed completely,the reaction mixture is gradually heated with continuous stirring. Afterthe polymerization reaction is initiated, the temperature of thereaction mixture is allowed to rise up to about 95° C. Once thepolymerization reaction is complete, the reaction mixture is cooled toroom temperature and the aqueous phase is removed. The solid can beisolated by filtration once water is added to the mixture. The filteredsolid is washed with water and then with a methanol/water mixture. Theresulting product is a crosslinked (methyl2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer.

As discussed herein, after polymerization, the product may be hydrolyzedor otherwise deprotected by methods known in the art. For hydrolysis ofthe polymer having ester groups to form a polymer having carboxylic acidgroups, preferably, the polymer is hydrolyzed with a strong base (e.g.,NaOH, KOH, Mg(OH)₂ or Ca(OH)₂) to remove the alkyl (e.g., methyl) groupand form the carboxylate salt. Alternatively, the polymer can behydrolyzed with a strong acid (e.g., HCl) to form the carboxylate salt.Preferably, the (methyl 2-fluoroacrylate)-divinylbenzene-1,7-octadieneterpolymer is hydrolyzed with an excess of aqueous sodium hydroxidesolution at a temperature from about 30° C. to about 100° C. to yield(sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer.Typically, the hydrolysis reaction is carried out for about 15 to 25hours. After hydrolysis, the solid is filtered and washed with waterand/or an alcohol.

The cation of the polymer salt formed in the hydrolysis reaction orother deprotection step depends on the base used in that step. Forexample, when sodium hydroxide is used as the base, the sodium salt ofthe polymer is formed. This sodium ion can be exchanged for anothercation by contacting the sodium salt with an excess of an aqueous metalsalt to yield an insoluble solid of the desired polymer salt. After thedesired ion exchange, the product is washed with an alcohol and/or waterand dried directly or dried after a dewatering treatment with denaturedalcohol; preferably, the product is washed with water and drieddirectly. For example, the sodium salt of the cation exchange polymer isconverted to the calcium salt by washing with a solution thatsubstitutes calcium for sodium, for example, by using calcium chloride,calcium acetate, calcium lactate gluconate, or a combination thereof.And, more specifically, to exchange sodium ions for calcium ions, the(sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer iscontacted with an excess of aqueous calcium chloride to yield aninsoluble solid of crosslinked (calcium2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer.

Using this suspension polymerization process, cross-linked polyMeFApolymer is isolated in good yield, generally above about 85%, morespecifically above about 90%, and even more specifically above about93%. The yield of the second step (i.e., hydrolysis) preferably occursin 100%, providing an overall yield above about 85%, more specificallyabove about 90%, and even more specifically above about 93%.

To add the linear polyol to the composition, the salt of the polymer isslurried with an aqueous solution of polyol (e.g., sorbitol), typicallywith the slurry containing an excess amount of polyol based on polymerweight. Performing this step can reduce inorganic fluoride in thecomposition. The slurry is maintained under conditions known to those ofskill in the art, such as for at least 3 hours and ambient temperatureand pressure. The solids are then filtered off and dried to desiredmoisture content.

The compositions of the invention are tested for their characteristicsand properties using a variety of established testing procedures. Forexample, the percent inorganic fluoride in the composition is tested bymixing a dried sample of composition with C-Wax in a defined proportion,and making a pellet by pressing it with a force of about 40 kN in analuminum cup. Percent fluorine content is analyzed by X-ray fluorescencein a manner known to those of skill in the art, for example, using aBruker AXS SRS 3400 (Bruker AXS, Wisconsin). In general, the amount oforganic fluorine in the composition is less than 25 wt. %, preferablyless than 20 wt. %, more preferably 7 wt. % to 25 wt. % and mostpreferably 7 wt. % to 20 wt. % based on the total weight of thecomposition. The percent calcium in the composition is tested afterextraction with an appropriate acid (e.g., 3M hydrochloric acid) usinginductively coupled plasma optical emission spectroscopy (ICP-OES)analysis in a manner known to those of skill in the art, for example,using a Thermo IRIS Intrepid II XSP (Thermo Scientific, Waltham, Mass.).In general, the amount of calcium in the polymer is in the range of fromabout 8 wt. % to about 25 wt. %, and preferably about 10 wt. % to about20 wt. %, based on the total weight of the polymer.

Also for example, the potassium binding capacity can be used for polymeror composition characterization. In this example, the potassium bindingcapacity is performed in vitro by weighing and transferringapproximately 300 mg of a dried sample of polymer or composition into a40 mL screw-top vial, and then adding a calculated volume of 200 mM KClsolution to achieve a concentration of 20 mg/mL of test substance. Thevial is shaken vigorously for two hours, and the supernatant is filteredthrough a 0.45 m filter followed by dilution to 1:20 in water. Thesupernatant is analyzed for potassium concentration via ICP-OES, and thepotassium binding is calculated using the following formula.

${{Potassium}\mspace{14mu} {binding}} = {\frac{20\mspace{11mu} ( {{dilution}\mspace{14mu} {factor}} )}{20\mspace{14mu} {mg}\text{/}{mL}\mspace{11mu} ( {{sample}\mspace{14mu} {conc}} )} \times ( {\lbrack K\rbrack_{blank} - \lbrack K\rbrack_{sample}} )\frac{{mmol}\mspace{14mu} K}{g\mspace{14mu} {polymer}}}$

One aspect of the invention is a method of removing potassium ions fromthe gastrointestinal tract of an animal subject in need thereof with acrosslinked cation exchange polymer or a pharmaceutical composition ofthe invention. The crosslinked cation exchange polymer generally has ahigh overall exchange capacity. The overall exchange capacity is themaximum amount of cations bound by the cation exchange polymer measuredin mEq/g. A higher exchange capacity is desired as it is a measure ofthe density of acid groups in the polymer and the more acid groups perunit weight, the greater the overall exchange capacity of the polymer.

The crosslinked cation exchange polymers and the compositions comprisinglinear polyol and crosslinked cation exchange polymer also generallyhave a high binding capacity for potassium. In particular, the in vivobinding capacity is relevant to therapeutic benefit in a patient.Generally, a higher in vivo binding capacity results in a morepronounced therapeutic effect. However, since patients can have a widerange of responses to the administration of cation exchange polymers,one measure of the in vivo binding capacity for potassium is the averagein vivo binding capacity calculated over a sample group. The term “highcapacity” as used herein encompasses an average in vivo binding of about1.0 mEq or more of potassium per gram of polymer.

One measure of the in vivo potassium binding capacity is the use of exvivo human aspirates. For this method, healthy patients are given a mealas a digestion mimic and aliquots of chyme are then sampled using a tubeplaced in the lumen of the small intestine and other portions of theintestines. For example, normal subjects are intubated with a doublelumen polyvinyl tube, with a mercury weighted bag attached to the end ofthe tube to facilitate movement of the tube into the small intestine.One aspiration aperture of the double lumen tube is located in thestomach and the other aperture is at the Ligament of Treitz (in theupper jejunum). Placement takes place with the use of fluoroscopy. Afterthe tube is placed, 550 mL of a liquid standard test meal (supplementedwith a marker, polyethylene glycol (PEG)−2 g/550 mL) is infused into thestomach through the gastric aperture at a rate of 22 mL per minute. Itrequires approximately 25 minutes for the entire meal to reach thestomach. This rate of ingestion simulates the duration of time requiredto eat normal meals. Jejunal chyme is aspirated from the tube whoselumen is located at the Ligament of Treitz. This fluid is collectedcontinuously during 30-minute intervals for a two and a half hourperiod. This process results in five specimens that are mixed, measuredfor volume, and lyophilized.

The potassium binding procedure is identical to the one described belowwith the non-interfering buffer experiment, except that the ex vivoaspirate liquid is used (after reconstitution of the freeze-driedmaterial in the proper amount of de-ionized water). The binding capacityin the ex vivo aspirate (VA) is calculated from the concentration ofpotassium in the aspirate with and without polymer. In some embodiments,the average ex vivo potassium binding capacity of a humangastrointestinal aspirate can be equal to or more than about 0.7 mEq pergram of polymer. More specifically, the ex vivo potassium bindingcapacity of a human gastrointestinal aspirate is about 0.8 mEq or moreper gram, more particularly is about 1.0 mEq or more per gram, even moreparticularly is about 1.2 mEq or more per gram, and most particularly isabout 1.5 mEq or more per gram.

Another measure of the in vivo binding capacity for potassium is the invitro binding capacity for potassium in non-interfering environment oran interfering environment at a particular pH. In a non-interferingenvironment, the crosslinked cation exchange polymer is placed in asolution having potassium ions as the only cation. This solution ispreferably at an appropriate GI physiological pH (e.g., about 6.5). Thein vitro binding capacity for potassium in a non-interfering environmentis a measure of the total binding capacity for cations.

Further, in an interfering environment, the environment contains cationsin concentrations relevant to the typical concentrations in thegastrointestinal tract and is at physiological pH (e.g., about 6.5). Inthe interfering environment, it is preferred that the polymer or thepharmaceutical composition exhibit selective binding for potassium ions.

In some embodiments, the in vitro potassium binding capacity isdetermined in solutions with a pH of about 5.5 or more. In variousembodiments, in vitro potassium binding capacity in a pH of about 5.5 ormore is equal to or more than 6 mEq per gram of polymer. A particularrange of in vitro potassium binding capacity in a pH of about 5.5 ormore is about 6 mEq to about 12 mEq per gram of polymer. Preferably thein vitro potassium binding capacity in a pH of about 5.5 or more isequal to about 6 mEq or more per gram, more particularly is about 7 mEqor more per gram, and even more particularly is about 8 mEq or more pergram.

The higher capacity of the polymer may enable the administration of alower dose of the pharmaceutical composition. Typically the dose of thepolymer used to obtain the desired therapeutic and/or prophylacticbenefits is about 0.5 gram/day to about 60 grams/day. A particular doserange is about 5 grams/day to about 60 grams/day, and more particularlyis about 5 grams/day to about 30 grams/day. In various administrationprotocols, the dose is administered about three times a day, forexample, with meals. In other protocols, the dose is administered once aday or twice a day. These doses can be for chronic or acuteadministration.

Polymers of the invention are crosslinked materials, meaning that theydo not generally dissolve in solvents, and, at most, swell in solvents.As used herein, “swelling ratio” refers to the number of grams ofsolvent taken up by one gram of otherwise non-solvated crosslinkedpolymer when equilibrated in an aqueous environment. When more than onemeasurement of swelling is taken for a given polymer, the mean of themeasurements is taken to be the swelling ratio.

The swelling ratio in physiological isotonic buffer, representative ofthe gastrointestinal tract, is typically in the range of about 1 toabout 7, specifically about 1 to 5; more particularly about 1 to 2. Insome embodiments, crosslinked cation exchange polymers of the inventionhave a swelling ratio of less than 5, or less than about 4, or less thanabout 3, or less than about 2.5, or less than about 2.

Generally, the polymers and pharmaceutical compositions described hereinretain a significant amount of the bound potassium, and specifically,the potassium bound by the polymer is not released prior to excretion ofthe polymer in the feces. The term “significant amount” as used hereinis not intended to mean that the entire amount of the bound potassium isretained prior to excretion. A sufficient amount of the bound potassiumis retained, such that a therapeutic and/or prophylactic benefit isobtained. Particular amounts of bound potassium that can be retainedrange from about 5% to about 100%. The polymer or pharmaceuticalcomposition should retain about 25% of the bound potassium, moreparticularly about 50%, even more particularly about 75% and mostparticularly retain about 100% of the bound potassium. The period ofretention is generally during the time that the polymer or compositionis being used therapeutically. In the embodiment in which the polymer orcomposition is used to bind and remove potassium from thegastrointestinal tract, the retention period is the time of residence ofthe polymer or composition in the gastrointestinal tract and moreparticularly the average residence time in the colon.

Generally, the cation exchange polymers are not significantly absorbedfrom the gastrointestinal tract. Depending upon the size distribution ofthe cation exchange polymer particles, clinically insignificant amountsof the polymers may be absorbed. More specifically, about 90% or more ofthe polymer is not absorbed, about 95% or more is not absorbed, evenmore specifically about 97% or more is not absorbed, and mostspecifically about 98% or more of the polymer is not absorbed.

In some embodiments of the invention, the polymers used in the inventionwill be administered unformulated (i.e., containing no additionalcarriers or other components). In other instances, a pharmaceuticalcomposition containing the polymer, a stabilizing linear polyol andoptionally water will be administered as described herein.

The methods, polymers and compositions described herein are suitable forremoval of potassium from a patient wherein a patient is in need of suchpotassium removal. For example, patients experiencing hyperkalemiacaused by disease and/or use of certain drugs benefit from suchpotassium removal. Further, patients at risk for developing high serumpotassium concentrations through use of agents that cause potassiumretention could be in need of potassium removal. The methods describedherein are applicable to these patients regardless of the underlyingcondition that is causing the high serum potassium levels.

Dosing regimens for chronic treatment of hyperkalemia can increasecompliance by patients, particularly for crosslinked cation exchangepolymers or compositions of the invention that are taken in gramquantities. The present invention is also directed to methods ofchronically removing potassium from an animal subject in need thereof,and in particular chronically treating hyperkalemia with a potassiumbinder that is a crosslinked aliphatic carboxylic polymer, andpreferably a pharmaceutical composition comprising a crosslinked cationexchange polymer and a linear polyol as described herein.

It has now been found that when using the crosslinked cation exchangepolymers and the compositions of the present invention, a once-a-daydose is substantially equivalent to a twice-a-day dose, which is alsosubstantially equivalent to a three-times-a-day dose. Generally, theonce per day or twice per day administration of a daily amount of thepolymer or the composition, has a potassium binding capacity of at least75% of the binding capacity of the same polymer or compositionadministered at the same daily amount three times per day. Morespecifically, the once per day or twice per day administration of adaily amount of the polymer or the composition has a potassium bindingcapacity of at least 80, 85, 90 or 95% of the binding capacity of thesame polymer or composition administered at the same daily amount threetimes per day. Even more specifically, the once per day or twice per dayadministration of a daily amount of the polymer or the composition has apotassium binding capacity of at least 80% of the binding capacity ofthe same polymer or composition administered at the same daily amountthree times per day. And even more specifically, the once per day ortwice per day administration of a daily amount of the polymer or thecomposition has a potassium binding capacity of at least 90% of thebinding capacity of the same polymer or composition administered at thesame daily amount three times per day. Most preferably, the once per dayor twice per day administration of a daily amount of the polymer or thecomposition has a potassium binding capacity that is not statisticallysignificantly different from the binding capacity of the same polymer orcomposition at the same daily amount administered three times per day.

Additionally, the invention is directed to methods of removing potassiumfrom an animal subject by administering a crosslinked cation exchangepolymer or a pharmaceutical composition comprising a crosslinked cationexchange polymer and an effective amount or from about 10 wt. % to about40 wt. % of a linear polyol to the subject once a day, wherein less than25% of subjects taking the polymer or composition once per dayexperience mild or moderate gastrointestinal adverse events.Gastrointestinal adverse events may include flatulence, diarrhea,abdominal pain, constipation, stomatitis, nausea and/or vomiting. Insome aspects, the polymer or composition is administered twice a day andless than 25% of subjects taking the polymer or composition twice perday experience mild or moderate gastrointestinal adverse events. In someinstances, the subjects taking the polymer or composition once per dayor twice per day experience no severe gastrointestinal adverse events.The crosslinked cation exchange polymers or pharmaceutical compositionsof the present invention have about 50% or more tolerability as comparedto the same polymer or composition of the same daily amount administeredthree times a day. For example, for every two patients in whichadministration of the polymer three times a day is well tolerated, thereis at least one patient in which administration of the polymer once aday or twice a day is well tolerated. The crosslinked cation exchangepolymers or pharmaceutical compositions have about 75% or moretolerability as compared to the same polymer or composition of the samedaily amount administered three times a day. It is also a feature ofthis invention that the cation exchange polymers or compositionsadministered once a day or twice a day have about 85% or moretolerability as the same polymer or composition of the same daily amountadministered three times a day. It is also a feature of this inventionthat the cation exchange polymers or compositions administered once aday or twice a day have about 95% or more tolerability as the samepolymer or composition of the same daily amount administered three timesa day. It is also a feature of this invention that the cation exchangepolymers or compositions administered once a day or twice a day haveabout substantially the same tolerability as the same polymer orcomposition of the same daily amount administered three times a day.

When administration is well tolerated, there should be little or nosignificant dose modification or dose discontinuation by the subject. Insome embodiments, well tolerated means there is no apparent doseresponse relationship for gastrointestinal adverse events. In some ofthese embodiments, well tolerated means that the followinggastrointestinal adverse effects are not reported from a statisticallysignificant number of subjects, including those effects selected fromthe group consisting of flatulence, diarrhea, abdominal pain,constipation, stomatitis, nausea and vomiting. In particular, theexamples also show that there were no severe gastrointestinal adverseevents in subjects.

In other embodiments, the present invention provides a method ofremoving potassium from the gastrointestinal tract of an animal subjectin need thereof, comprising administering an effective amount of acrosslinked cation exchange polymer or a composition comprising acrosslinked cation exchange polymer and a linear polyol once per day ortwice per day to the subject, wherein the polymer or composition is aswell tolerated as administering substantially the same amount of thesame polymer or composition three times per day. In some instances, thesubject is experiencing hyperkalemia and thus the method treatshyperkalemia. In other instances, the method lowers serum potassium. Inparticular embodiments, the potassium polymer is a crosslinked aliphaticcarboxylic polymer.

The compositions and/or methods of this invention include a compositioncomprising a crosslinked cation exchange polymer and an effective amountor from about 10 wt. % to about 40 wt. % linear polyol that extractsfrom an animal subject in need thereof about 5% more potassium ascompared to the same dose and same administration frequency of the samecomposition that does not contain the linear polyol. More specifically,the compositions and/or methods include a composition of the inventionthat extracts from an animal subject in need thereof about 10% morepotassium as compared to the same dose and same administration frequencyof the same composition that does not contain the linear polyol. Andeven more specifically, the compositions and/or methods include acomposition of the invention that extracts from an animal subject inneed thereof about 15% or about 20% more potassium as compared to thesame dose and same administration frequency of the otherwise samecomposition that does not include the linear polyol.

As shown in the examples, volunteers receiving a composition comprisinga calcium salt of crosslinked poly-alpha-fluoroacrylic acid and fromabout 10 wt. % to about 40 wt. % of a linear polyol once per dayexcreted 82.8% of the amount of fecal potassium as those volunteers whoreceived substantially the same amount of the same polymer three-timesper day. It is also shown that volunteers receiving a compositioncomprising a calcium salt of cross-linked poly-alpha-fluoroacrylic acidand from about 10 wt. % to about 40 wt. % of a linear polyol twice perday excreted 91.5% of the amount of fecal potassium as those volunteerswho received substantially the same amount of the same polymerthree-times per day. Fecal excretion is an in vivo measure of efficacythat relates to the lowering of serum potassium in subjects in needthereof.

These results were not based on administration with meals nor were theybased on any particular formulation. In particular, the potassiumbinding polymers or compositions of this invention are substantiallyunreactive with food and can be added to typical food products (e.g.,water, pudding, apple sauce, baked goods, etc.), which adds tocompliance enhancement (particularly for patients who are on a waterrestricted diet). Substantially unreactive in this context means thatthe polymers or compositions do not effectively change the taste,consistency or other noticeable properties of the food in which it ismixed or placed. Also, the polymers or compositions of this inventioncan be administered without regard to mealtime. In fact, since potassiumbeing bound is not just from meals, but is potassium that is excretedinto the gastrointestinal tract, administration can take place at anytime. Dosing regimens also take into account the other embodimentsdiscussed herein, including capacity, amount and form.

If necessary, the crosslinked cation exchange polymers or compositionscomprising a crosslinked cation exchange polymer and a linear polyol maybe administered in combination with other therapeutic agents. The choiceof therapeutic agents that can be co-administered with the compounds ofthe invention will depend, in part, on the condition being treated.

Further, patients suffering from chronic kidney disease and/orcongestive heart failure can be particularly in need of potassiumremoval because agents used to treat these conditions may causepotassium retention in a significant population of these patients. Forthese patients, decreased renal potassium excretion results from renalfailure (especially with decreased glomerular filtration rate), oftencoupled with the ingestion of drugs that interfere with potassiumexcretion, e.g., potassium-sparing diuretics, angiotensin-convertingenzyme inhibitors (ACEs), angiotensin receptor blockers (ARBs), betablockers, renin inhibitors, aldosterone synthase inhibitors,non-steroidal anti-inflammatory drugs, heparin, or trimethoprim. Forexample, patients suffering from chronic kidney disease can beprescribed various agents that will slow the progression of the disease;for this purpose, angiotensin-converting enzyme inhibitors (ACEs),angiotensin receptor blockers (ARBs), and aldosterone antagonists arecommonly prescribed. In these treatment regimens theangiotensin-converting enzyme inhibitor is captopril, zofenopril,enalapril, ramipril, quinapril, perindopril, lisinopril, benazipril,fosinopril, or combinations thereof and the angiotensin receptor blockeris candesartan, eprosartan, irbesartan, losartan, olmesartan,telmisartan, valsartan, or combinations thereof and the renin inhibitoris aliskiren. The aldosterone antagonists can also cause potassiumretention. Thus, it can be advantageous for patients in need of thesetreatments to also be treated with an agent that removes potassium fromthe body. The aldosterone antagonists typically prescribed arespironolactone, eplerenone, and the like.

In certain particular embodiments, the crosslinked cation exchangepolymers or compositions described herein can be administered on aperiodic basis to treat a chronic condition. Typically, such treatmentswill enable patients to continue using drugs that may causehyperkalemia, such as potassium-sparing diuretics, ACEs, ARBs,aldosterone antagonists, β-blockers, renin inhibitors, non-steroidalanti-inflammatory drugs, heparin, trimethoprim, or combinations thereof.Also, use of the polymeric compositions described herein will enablecertain patient populations, who were unable to use certainabove-described drugs, to use such drugs.

In certain use situations, the crosslinked cation exchange polymers usedare those that are capable of removing less than about 5 mEq ofpotassium per day, or in the range of about 5 mEq to about 60 mEq ofpotassium per day.

In certain other embodiments, the compositions and methods describedherein are used in the treatment of hyperkalemia in patients in needthereof, for example, when caused by excessive intake of potassium.Excessive potassium intake alone is an uncommon cause of hyperkalemia.More often, hyperkalemia is caused by indiscriminate potassiumconsumption in a patient with impaired mechanisms for the intracellularshift of potassium or renal potassium excretion.

In the present invention, the crosslinked cation exchange polymers orcompositions comprising a crosslinked cation exchange polymer and alinear polyol can be co-administered with other active pharmaceuticalagents. This co-administration can include simultaneous administrationof the two agents in the same dosage form, simultaneous administrationin separate dosage forms, and separate administration. For example, forthe treatment of hyperkalemia, the crosslinked cation exchange polymeror composition of the invention can be co-administered with drugs thatcause the hyperkalemia, such as potassium-sparing diuretics,angiotensin-converting enzyme inhibitors (ACEs), angiotensin receptorblockers (ARBs), beta blockers, renin inhibitors, non-steroidalanti-inflammatory drugs, heparin, or trimethoprim. In particular, thecrosslinked cation exchange polymer or composition can beco-administered with ACEs (e.g., captopril, zofenopril, enalapril,ramipril, quinapril, perindopril, lisinopril, benazipril, andfosinopril), ARBs (e.g., candesartan, eprosartan, irbesartan, losartan,olmesartan, telmisartan, and valsartan) and renin inhibitors (e.g.aliskiren). In particular embodiments, the agents are simultaneouslyadministered, wherein both the agents are present in separatecompositions. In other embodiments, the agents are administeredseparately in time (i.e., sequentially).

The term “treating” as used herein includes achieving a therapeuticbenefit. By therapeutic benefit is meant eradication, amelioration, orprevention of the underlying disorder being treated. For example, in ahyperkalemia patient, therapeutic benefit includes eradication oramelioration of the underlying hyperkalemia. Also, a therapeutic benefitis achieved with the eradication, amelioration, or prevention of one ormore of the physiological symptoms associated with the underlyingdisorder such that an improvement is observed in the patient,notwithstanding that the patient may still be afflicted with theunderlying disorder. For example, administration of a potassium-bindingpolymer to a patient experiencing hyperkalemia provides therapeuticbenefit not only when the patient's serum potassium level is decreased,but also when an improvement is observed in the patient with respect toother disorders that accompany hyperkalemia, like renal failure. In sometreatment regimens, the crosslinked cation exchange polymer orcomposition of the invention may be administered to a patient at risk ofdeveloping hyperkalemia or to a patient reporting one or more of thephysiological symptoms of hyperkalemia, even though a diagnosis ofhyperkalemia may not have been made.

The pharmaceutical compositions of the present invention includecompositions wherein the crosslinked cation exchange polymers arepresent in an effective amount, i.e., in an amount effective to achievetherapeutic or prophylactic benefit. The actual amount effective for aparticular application will depend on the patient (e.g., age, weight,etc.), the condition being treated, and the route of administration.Determination of an effective amount is well within the capabilities ofthose skilled in the art, especially in light of the disclosure herein.The effective amount for use in humans can be determined from animalmodels. For example, a dose for humans can be formulated to achievegastrointestinal concentrations that have been found to be effective inanimals.

The polymers and compositions described herein can be used as foodproducts and/or food additives. They can be added to foods prior toconsumption or while packaging. The polymers and compositions can alsobe used in fodder for animals to lower potassium levels, which isdesirable in fodders for pigs and poultry to lower the water secretion.

The crosslinked cation exchange polymers or pharmaceutically acceptablesalts thereof, or compositions described herein, can be delivered to thepatient using a wide variety of routes or modes of administration. Themost preferred routes for administration are oral, intestinal, orrectal. Rectal routes of administration are known to those of skill inthe art. Intestinal routes of administration generally refer toadministration directly into a segment of the gastrointestinal tract,e.g., through a gastrointestinal tube or through a stoma. The mostpreferred route for administration is oral.

The polymers (or pharmaceutically acceptable salts thereof) may beadministered per se or in the form of a pharmaceutical compositionwherein the active compound(s) is in admixture or mixture with one ormore pharmaceutically acceptable excipients. Pharmaceutical compositionsfor use in accordance with the present invention may be formulated inconventional manner using one or more pharmaceutically acceptableexcipients comprising carriers, diluents, and auxiliaries whichfacilitate processing of the active compounds into preparations whichcan be used physiologically. Proper composition is dependent upon theroute of administration chosen.

For oral administration, the polymers or compositions of the inventioncan be formulated readily by combining the polymer or composition withpharmaceutically acceptable excipients well known in the art. Suchexcipients enable the compositions of the invention to be formulated astablets, pills, dragees, capsules, liquids, gels, syrups, slurries,suspensions, wafers, and the like, for oral ingestion by a patient to betreated. In one embodiment, the oral composition does not have anenteric coating. Pharmaceutical preparations for oral use can beobtained as a solid excipient, optionally grinding a resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients are, in particular, fillers such as sugars, including lactoseor sucrose; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone (PVP); and variousflavoring agents known in the art. If desired, disintegrating agents maybe added, such as the cross-linked polyvinyl pyrrolidone, agar, oralginic acid or a salt thereof such as sodium alginate.

In various embodiments, the active ingredient (e.g., polymer)constitutes over about 20%, more particularly over about 40%, even moreparticularly over about 50%, and most particularly more than about 60%by weight of the oral dosage form, the remainder comprising suitableexcipient(s). In compositions containing water and linear polyol, thepolymer preferably constitutes over about 20%, more particularly overabout 40%, and even more particularly over about 50% by weight of theoral dosage form.

In some embodiments, pharmaceutical compositions are in the form ofliquid compositions. In various embodiments, the pharmaceuticalcomposition contains a crosslinked cation exchange polymer dispersed ina suitable liquid excipient. Suitable liquid excipients are known in theart; see, e.g., Remington's Pharmaceutical Sciences.

Unless otherwise indicated, an alkyl group as described herein alone oras part of another group is an optionally substituted linear saturatedmonovalent hydrocarbon radical containing from one to twenty carbonatoms and preferably one to eight carbon atoms, or an optionallysubstituted branched saturated monovalent hydrocarbon radical containingthree to twenty carbon atoms, and preferably three to eight carbonatoms. Examples of unsubstituted alkyl groups include methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl,i-pentyl, s-pentyl, t-pentyl, and the like.

The term “amide moiety” as used herein represents a bivalent (i.e.,difunctional) group including at least one amido linkage

such as —C(O)—NR_(A)—R_(C)—NR_(B)—C(O)— wherein R_(A) and R_(B) areindependently hydrogen or alkyl and R_(C) is alkylene. For example, anamide moiety can be —C(O)—NH—(CH₂)_(p)—NH—C(O)— wherein p is an integerof 1 to 8.

The term “aryl” as used herein alone or as part of another group denotesan optionally substituted monovalent aromatic hydrocarbon radical,preferably a monovalent monocyclic or bicyclic group containing from 6to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl,substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyland substituted phenyl are the more preferred aryl groups. The term“aryl” also includes heteroaryl.

The terms “carboxylic acid group”, “carboxylic” or “carboxyl” denote themonovalent radical —C(O)OH. Depending upon the pH conditions, themonovalent radical can be in the form —C(O)O⁻Q⁺ wherein Q⁺ is a cation(e.g., sodium), or two of the monovalent radicals in close proximity canbond with a divalent cation Q²⁺ (e.g., calcium, magnesium), or acombination of these monovalent radicals and —C(O)OH are present.

The term “cycloalkyl” as used herein denotes optionally an optionallysubstituted cyclic saturated monovalent bridged or non-bridgedhydrocarbon radical containing from three to eight carbon atoms in onering and up to 20 carbon atoms in a multiple ring group. Exemplaryunsubstituted cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, norbornyl,and the like.

The term “-ene” as used as a suffix as part of another group denotes abivalent radical in which a hydrogen atom is removed from each of twoterminal carbons of the group, or if the group is cyclic, from each oftwo different carbon atoms in the ring. For example, alkylene denotes abivalent alkyl group such as methylene (—CH₂—) or ethylene (—CH₂CH₂—),and arylene denotes a bivalent aryl group such as o-phenylene,m-phenylene, or p-phenylene.

The term “ether moiety” as used herein represents a bivalent (i.e.,difunctional) group including at least one ether linkage (i.e., —O—).For example, in Formulae 3 or 33 as defined herein, the ether moiety canbe —R_(A)OR_(B)— or —R_(A)OR_(C)OR_(B)— wherein R_(A), R_(B) and R_(C)are independently alkylene.

The term “heteroaryl,” as used herein alone or as part of another group,denotes an optionally substituted monovalent monocyclic or bicyclicaromatic radical of 5 to 10 ring atoms, where one or more, preferablyone, two, or three, ring atoms are heteroatoms independently selectedfrom N, O, and S, and the remaining ring atoms are carbon. Exemplaryheteroaryl moieties include benzofuranyl, benzo[d]thiazolyl,isoquinolinyl, quinolinyl, thiophenyl, imidazolyl, oxazolyl, quinolinyl,furanyl, thazolyl, pyridinyl, furyl, thienyl, pyridyl, oxazolyl,pyrrolyl, indolyl, quinolinyl, isoquinolinyl, and the like.

The term “heterocyclo,” as used herein alone or as part of anothergroup, denotes a saturated or unsaturated monovalent monocyclic group of4 to 8 ring atoms, in which one or two ring atoms are heteroatom(s),independently selected from N, O, and S, and the remaining ring atomsare carbon atoms. Additionally, the heterocyclic ring may be fused to aphenyl or heteroaryl ring, provided that the entire heterocyclic ring isnot completely aromatic. Exemplary heterocyclo groups include theheteroaryl groups described above, pyrrolidino, piperidino, morpholino,piperazino, and the like.

The term “hydrocarbon” as used herein describes a compound or radicalconsisting exclusively of the elements carbon and hydrogen.

The term “phosphonic” or “phosphonyl” denotes the monovalent radical

The term “phosphoric” or “phosphoryl” denotes the monovalent radical

The term “protected” as used herein as part of another group denotes agroup that blocks reaction at the protected portion of a compound whilebeing easily removed under conditions that are sufficiently mild so asnot to disturb other substituents of the compound. For example, aprotected carboxylic acid group-C(O)OP_(g) or a protected phosphoricacid group —OP(O)(OH)OP_(g) or a protected phosphonic acid group—P(O)(OH)OP_(g) each have a protecting group P_(g) associated with theoxygen of the acid group wherein P_(g) can be alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl,i-pentyl, s-pentyl, t-pentyl, and the like), benzyl, silyl (e.g.,trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),triphenylsilyl (TPS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS) and the like. A variety of protecting groups and the synthesisthereof may be found in “Protective Groups in Organic Synthesis” by T.W.Greene and P.G.M. Wuts, John Wiley & Sons, 1999. When the term“protected” introduces a list of possible protected groups, it isintended that the term apply to every member of that group. That is, thephrase “protected carboxylic, phosphonic or phosphoric” is to beinterpreted as “protected carboxylic, protected phosphonic or protectedphosphoric.” Likewise, the phrase “optionally protected carboxylic,phosphoric or phosphonic” is to be interpreted as “optionally protectedcarboxylic, optionally protected phosphonic or optionally protectedphosphoric.”

The term “substituted” as in “substituted aryl,” “substituted alkyl,”and the like, means that in the group in question (i.e., the alkyl, arylor other group that follows the term), at least one hydrogen atom boundto a carbon atom is replaced with one or more substituent groups such ashydroxy (—OH), alkylthio, phosphino, amido

(—CON(R_(A))(R_(B)), wherein R_(A) and R_(B) are independently hydrogen,alkyl, or aryl), amino(—N(R_(A))(R_(B)), wherein R_(A) and R_(B) areindependently hydrogen, alkyl or aryl), halo (fluoro, chloro, bromo, oriodo), silyl, nitro (—NO₂), an ether (—OR_(A) wherein R_(A) is alkyl oraryl), an ester (—OC(O)R_(A) wherein R_(A) is alkyl or aryl), keto(—C(O)R_(A) wherein R_(A) is alkyl or aryl), heterocyclo, and the like.When the term “substituted” introduces a list of possible substitutedgroups, it is intended that the term apply to every member of thatgroup. That is, the phrase “optionally substituted alkyl or aryl” is tobe interpreted as “optionally substituted alkyl or optionallysubstituted aryl.”

Having described the invention in detail, it will be apparent thatmodifications and variations are possible without departing from thescope of the invention defined in the appended claims.

EXAMPLES

The following non-limiting examples are provided to further illustratethe present invention.

Materials for Examples 1-5.

Methyl 2-fluoroacrylate (MeFA; SynQuest Labs) contained 0.2 wt %hydroquinone and was vacuum distilled before use. Divinylbenzene (DVB;Aldrich) was technical grade, 80%, mixture of isomers. 1,7-octadiene(ODE 98%; Aldrich), lauroyl peroxide (LPO 99%; ACROS Organics),polyvinyl alcohol (PVA typical molecular weight 85,000-146,000, 87-89%hydrolyzed; Aldrich), sodium chloride (NaCl; Aldrich), sodium phosphatedibasic heptahydrate (Na₂HPO₄ 7H₂O; Aldrich), and sodium phosphatemonobasic monohydrate (NaH₂PO₄H₂O; Aldrich) were used as received.

Example 1: DVB as Crosslinking Monomer

The polymerization was carried out in a 1 L three-neck Morton-type roundbottom flask equipped with an overhead mechanical stirrer with a Teflonpaddle and a water condenser. An organic phase was prepared by mixingMeFA (54 g), DVB (6 g) and LPO (0.6 g), and an aqueous phase wasprepared by dissolving PVA (3 g) and NaCl (11.25 g) in water (285.75 g).The organic and aqueous phases were then mixed in the flask and stirredat 300 rpm under nitrogen. The flask was immersed in a 70° C. oil bathfor 3 hours, and cooled to room temperature. The internal temperatureduring the reaction was about 65° C. The solid product was washed withwater and collected by decanting off supernatant solution. The whitesolid was freeze-dried, affording dry solid polyMeFA particles (orbeads) (56.15 g, 94%).

Hydrolysis was carried out in the same setup as for the polymerization.PolyMeFA particles (48.93 g) from above were suspended in KOH solution(500 g, 10 wt. %) and stirred at 300 rpm. The mixture was heated in a95° C. oil bath for 20 hours and cooled to room temperature. The solidproduct was washed with water and collected by decanting off thesupernatant solution. After freeze-drying, poly fluoroacrylic acid(polyFAA) particles (48.54 g, 82%) were obtained. These particles werein the form of beads.

Example 2: Polymer Synthesis Using Two Crosslinking Monomers

Multiple suspension polymerizations were carried out in a mannersubstantially similar to Example 1. The synthesis conditions and resultsare summarized in Table 1. Compared to Example 1, the addition of ODE asa second crosslinker in all ratios tested increased the yield after thehydrolysis step. Therefore the overall yield for polyFAA bead synthesiswas improved to a level of greater than 90%.

TABLE 1 Synthesis conditions and selected properties Aqueous PhaseOrganic Phase pH before H after MeFA DVB ODE Yield Swelling BC Exp #Buffer NaCl polymz polymz wt. % wt. % wt. % Susp. Hydro. Overall Ratiommol/g Comp 1 no 3.75% nm 4.00 95 5 0 98% 64% 63% 2.66 9.59 Comp 2 no3.75% nm 3.90 90 10 0 94% 82% 77% 1.52 8.72 Comp 3 no 3.75% nm 3.50 8020 0 89% 90% 80% 1.01 5.96 Ex 789 no 3.75% 5.10 3.50 90 8 2 95% 100% 95% 1.58 8.70 Ex 792 0.25% 3.50% 8.30 3.95 94% 100%  94% 1.49 8.76 Ex793 0.50% 3.25% 8.45 5.28 94% 95% 89% 1.44 8.62 Ex 808 0.50% 3.25% nm nmnm nm 92% nm 8.76 Ex 811 0.50% 3.25% 7.25 5.05 nm nm 93% nm nm Ex 8150.75% 2.50% 7.24 5.26 nm nm 88% nm nm Ex 816 0.75% 2.50% 7.16 4.62 87%94% 82% nm nm Ex 814 1.00% 0.00% 7.66 5.51 aggregates nm nm Ex 794 no3.75% 5.78 nm 90 5 5 95% 100%  95% 1.57 9.26 Ex 803 no 3.75% 5.17 3.94nm nm 95% 1.44 8.70 Ex 805 0.50% 3.25% 7.00 5.23 nm nm 95% 1.51 8.70 Ex812 0.50% 3.25% 7.29 5.21 nm nm 95% nm nm Ex 801 no 3.75% 5.18 3.11 90 28 93% 100% 93% 1.80 9.05 Ex 806 0.50% 3.25% 7.00 5.44 nm nm 94% 1.678.21 Ex 796 no 3.75% nm nm 90 0 10 87% 98% 85% 2.34 9.87 Ex 800 0.50%3.25% 8.24 4.93 90 0 10 92% 95% 87% 2.51 9.46 Ex 802 0.50% 3.25% 8.275.44 85 0 15 88% 95% 84% 2.33 8.98 Note: (1) buffer, Na₂HPO₄/NaH₂PO₄;(2) swelling ratio, measured using salt form; (3) BC, binding capacity,measured using H form in 100 mM KOH solution; (4) In Ex 816, 200 ppmNaNO₂ was added in aqueous phase; (5) nm, means not measured; (6) polymzmeans polymerization; (7) Susp. means suspension; (8) Hydro. meanshydrolysis.

Examples 3-5: Synthesis of FAA Beads with DVB/ODE

The polymers of examples 3-5 were prepared as follows. A polymerizationwas carried out in a 1 L three-neck Morton-type round bottom flaskequipped with an overhead mechanical stirrer with a Teflon paddle and awater condenser. An organic phase was prepared by mixing MeFA, DVB, ODEand LPO (0.6 g), and an aqueous phase was prepared by dissolving PVA (3g) and NaCl (11.25 g) in water (285.75 g). The organic and aqueousphases were then mixed in the flask, and stirred at 300 rpm undernitrogen. The flask was immersed in a 70° C. oil bath for 5 hours, andcooled to room temperature. The internal temperature during reaction wasabout 65° C. The solid product was washed with water and collected byfiltration. The white solid was freeze-dried, affording dry solidpolyMeFA beads.

Hydrolysis was carried out in the same setup as for the polymerization.PolyMeFA beads from the polymerization reaction were suspended in a NaOHsolution (400 g, 10 wt %) and stirred at 200 rpm. The mixture was heatedin a 95° C. oil bath for 20 hours and cooled to room temperature. Thesolid product was washed with water and collected by filtration. Afterfreeze-drying, polyFAA beads were obtained. The synthesis conditions andselected properties are summarized below:

Organic Phase Hydrolysis Yield MeFA DVB ODE MeFA DVB ODE polyMeFA Susp.Exm # (g) (g) (g) wt. % wt. wt. (g) (g), % Hydro. (g), % 3 54 4.8 1.2 908 2 40.26 56.74, 43.16, 100% 95% 4 54 3 3 90 5 5 39.17 56.91, 42.31,100% 95% 5 54 1.2 4.8 90 2 8 38.23 55.94, 41.62, 100% 93%

The calcium form of the polyFAA beads of Example 4 was prepared byexposing the (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadienecopolymer to an excess of aqueous calcium chloride solution to yieldinsoluble cross-linked (calcium2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer. After thecalcium ion exchange, the Ca(polyFAA) final product was washed withethanol and water.

Example 6: Preparation of Compositions with Ca(polyFAA) and StabilizingPolyol and Stability Testing of Such Compositions During Storage

Composition Preparation: To a 500 mL 3-necked round bottom flaskequipped with a magnetic stirrer and nitrogen inlet adapter was chargedD-sorbitol (60 g; 0.3 moles) followed by 240 g of water. The mixture wasstirred until a clear solution was obtained. Ca(polyFAA) (30 g) preparedby the process described in Example 4 was added in one portion to thesorbitol solution and the resultant slurry was stirred at ambienttemperature (20-25° C.) for three hours. The solids were filtered offand dried under reduced pressure to the desired water content. Thesolids (35.lg) were analyzed for sugar alcohol content, loss on drying(LOD), and calcium content. This same sample preparation technique wasused for the other compositions, with the specific details of varyingD-sorbitol concentrations, times of mixing and drying as set forth inTable 2.

The samples prepared as discussed above were placed in storage at thetemperatures and times listed in Tables 3-12. For the samples stored at5° C. and ambient temperature, the samples were transferred to a vial,which was placed in a Sure-Seal bag and sealed, and then placed in asecond Sure-Seal bag with a desiccant (calcium sulfate) in the secondbag, which was also sealed. For the samples at higher temperatures, thesamples were placed in vials and stored at the stated temperatures. Atthe specified time (1 week, 3 weeks, 5 weeks, 7 weeks, etc.), aliquotsof the samples were removed from storage and tested for their weight,moisture content, LOD and free inorganic fluoride. These tests werecarried out as detailed in the specification above. Fluorideconcentrations shown in Tables 6A to 6J below have been corrected forwater and polyol weight.

TABLE 2 SORBITOL Ex- CONCENTRATION am- USED FOR SORBITOL ple LOADINGLOADING MIXING DRYING No. (W/W %) (W/W %) TIME METHOD 6A 2 3.1 1.5 h  lyophilization 6B 5 7.3 3 h lyophilization 6C 10 12.3 3 h lyophilization6D 20 17.2 3 h lyophilization 6E 20 18.3 3 h air dried under vacuum 6F20 18.3 3 h lyophilization 6G 30 22.5 1.5 h   air dried under vacuum 6H30 22.5 3 h lyophilization 6I 45 24.9 3 h air dried under vacuum 6J 4524.9 1.5 h   lyophilization

TABLE 3 Sample 6A Mois- Sample STORAGE Sample ture Dry Fluoride FluorideTIME CONDI- Weight Content Weight Reading Conc. POINT TIONS (g) (%) (g)(ppm) (ug/g) T = 0 5-8° C. 0.498 4.80 0.474 2.79 607 20-25° C. 40° C. T= 1 5-8° C. 0.496 5.72 0.468 3.04 671 WEEK 20-25° C. 0.504 6.00 0.4744.53 987 40° C. 0.545 5.48 0.515 9.79 1961 T = 3 5-8° C. 0.508 4.990.483 3.53 754 WEEKS 20-25° C. 0.505 4.97 0.480 6.28 1351 40° C. n/a n/an/a n/a n/a T = 5 5-8° C. 0.315 8.06 0.290 4.69 1003 WEEKS 20-25° C.0.317 6.03 0.298 7.33 1523 40° C. n/a n/a n/a n/a n/a T = 7 5-8° C.0.513 8.06 0.472 4.6  1006 WEEKS 20-25° C. 0.513 6.03 0.482 7.63 607 40°C. n/a n/a n/a n/a n/a

TABLE 4 Sample 6B Mois- Sample STORAGE Sample ture Dry Fluoride FluorideTIME CONDI- Weight Content Weight Reading Conc. POINT TIONS (g) (%) (g)(ppm) (ug/g) T = 0 5-8° C. 0.514 5.34 0.487 1.74 385 20-25° C. 40° C. T= 1 5-8° C. 0.537 6.31 0.503 1.99 427 WEEK 20-25° C. 0.518 6.57 0.4843.08 686 40° C. 0.52 7.03 0.483 7.03 1569 T = 3 5-8° C. 0.513 5.21 0.4862.15 477 WEEKS 20-25° C. 0.501 6.07 0.471 4.3  986 40° C. n/a n/a n/an/a n/a T = 5 5-8° C. 0.5031 5.97 0.473 2.77 632 WEEKS 20-25° C. 0.50926.79 0.475 5.17 1175 40° C. n/a n/a n/a n/a n/a T = 7 5-8° C. 0.507 5.970.477 2.76 625 WEEKS 20-25° C. 0.508 6.79 0.474 5.67 1291 40° C. n/a n/an/a n/a n/a T = 9 5-8° C. 0.504 5.97 0.474 2.81 640 WEEKS 20-25° C. n/an/a n/a n/a n/a 40° C. n/a n/a n/a n/a n/a

TABLE 5 Sample 6C Mois- Sample STORAGE Sample ture Dry Fluoride FluorideTIME CONDI- Weight Content Weight Reading Conc. POINT TIONS (g) (%) (g)(ppm) (ug/g) T = 0 5-8° C. 0.512 5.98 0.481 1.1  228.7 20-25° C. 40° C.T = 1 5-8° C. 0.576 5.98 0.542 1.28 269 WEEK 20-25° C. 0.506 5.71 0.4771.88 449 40° C. 0.52 5.63 0.491 4.61 1071 T = 3 5-8° C. 0.527 6.86 0.4911.3  302 WEEKS 20-25° C. 0.512 6.56 0.478 2.46 586 40° C. 0.506 6.740.472 6.44 1556 T = 5 5-8° C. 0.5104 7.19 0.474 1.80 433 WEEKS 20-25° C.0.5118 6.95 0.476 3.29 788 40° C. n/a n/a n/a n/a n/a T = 7 5-8° C.0.513 7.19 0.476 1.75 420 WEEKS 20-25° C. 0.521 6.95 0.485 3.4  799 40°C. 0.508 6.74 0.474 7.84 1887 T = 9 5-8° C. 0.527 7.19 0.489 1.81 422WEEKS 20-25° C. n/a n/a n/a n/a n/a 40° C. n/a n/a n/a n/a n/a

TABLE 6 Sample 6D Mois- Sample STORAGE Sample ture Dry Fluoride FluorideTIME CONDI- Weight Content Weight Reading Conc. POINT TIONS (g) (%) (g)(ppm) (ug/g) T = 0 5-8° C. 0.517 7.41 0.479 0.5 126 20-25° C. 40° C. T =1 5-8° C. 0.503 7.52 0.465 0.649 169 WEEK 20-25° C. 0.534 8.2 0.490 1.03254 40° C. 0.562 6.95 0.523 2.55 589 T = 3 5-8° C. 0.525 6.73 0.4900.659 163 WEEKS 20-25° C. 0.524 6.91 0.488 1.2 297 40° C. 0.514 6.630.480 2.75 692 T = 5 5-8° C. 0.5157 7.08 0.479 0.819 207 WEEKS 20-25° C.0.5062 7.56 0.468 1.47 379 40° C. 0.5416 8.8 0.494 4.15 1014 T = 7 5-8°C. 0.525 7.08 0.488 0.809 200 WEEKS 20-25° C. 0.519 7.56 0.480 1.65 41540° C. 0.524 8.8 0.478 4.56 1152 T = 9 5-8° C. 0.513 7.56 0.474 0.734187 WEEKS 20-25° C. n/a n/a n/a n/a n/a 40° C. n/a n/a n/a n/a n/a

TABLE 7 Sample 6E Mois- STORAGE ture Dry Fluoride Fluoride TIME CONDI-Sample Content Weight Reading Conc. POINT TIONS Wt (g) (%) (g) (ppm)(ug/g) T = 0 5-8° C. 0.55 17.00 0.457 0.05 13 20-25° C. 40° C. T = 25-8° C. 0.504 16.53 0.421 0.04 12 WEEKS 20-25° C. 0.507 16.30 0.424 0.0823 40° C. 0.507 16.20 0.425 0.75 217 T = 4 5-8° C. 0.519 16.60 0.4330.04 11 WEEKS 20-25° C. 0.508 15.60 0.429 0.09 26 40° C. 0.513 13.500.444 0.95 262 T = 6 5-8° C. 0.506 15.34 0.428 0.03 9 WEEKS 20-25° C.0.511 15.57 0.431 0.05 15 40° C. 0.507 14.72 0.432 1.35 382 T = 8 5-8°C. 0.514 16.81 0.428 0.04 11 WEEKS 20-25° C. 0.5 16.09 0.420 0.06 17 40°C. 0.511 14.28 0.438 1.36 379 T = 9 5-8° C. 0.509 17.11 0.422 0.05 15WEEKS 20-25° C. 0.502 16.00 0.422 0.28 81 40° C. 0.525 15.60 0.443 2.03561 T = 10 5-8° C. 0.514 17.19 0.426 0.05 15 WEEKS 20-25° C. 0.524 15.560.442 0.31 86 40° C. 0.502 15.10 0.426 2.2 632 T = 12 5-8° C. 0.50317.20 0.416 0.26 7 WEEKS 20-25° C. 0.505 15.60 0.426 6.3 181 40° C.0.514 15.10 0.436 2.46 690

TABLE 8 Sample 6F Mois- Sample STORAGE ture Dry Fluoride Fluoride TIMECONDI- Sample Content Weight Reading Conc. POINT TIONS Wt (g) (%) (g)(ppm) (ug/g) T = 0 5-8° C. 0.519 6.85 0.483 0.16 39 20-25° C. 40° C. T =2 5-8° C. 0.504 8.08 0.463 0.15 39 WEEKS 20-25° C. 0.557 7.78 0.514 0.58138 40° C. 0.516 9.55 0.467 1.40 367 T = 4 5-8° C. 0.533 8.33 0.489 0.1640 WEEKS 20-25° C. 0.540 7.40 0.500 0.56 137 40° C. 0.510 7.50 0.4722.25 584 T = 6 5-8° C. 0.507 7.74 0.468 0.09 23 WEEKS 20-25° C. 0.5017.14 0.465 0.55 144 40° C. 0.504 7.59 0.466 2.39 628 T = 8 5-8° C. 0.5037.88 0.463 0.08 21 WEEKS 20-25° C. 0.502 7.54 0.464 0.53 140 40° C.0.510 8.59 0.466 2.36 619 T = 9 5-8° C. 0.509 7.49 0.471 0.33 86 WEEKS20-25° C. 0.509 7.57 0.470 1.05 273 40° C. 0.492 8.04 0.452 2.61 706 T =10 5-8° C. 0.503 7.49 0.465 0.33 87 WEEKS 20-25° C. 0.52 7.57 0.481 1.12285 40° C. 0.504 8.04 0.463 3.03 800 T = 12 5-8° C. 0.502 7.49 0.4642.48 65 WEEKS 20-25° C. 0.504 7.57 0.466 6.82 179 40° C. 0.498 8.040.458 4.02 1075

TABLE 9 Sample 6G Mois- Sample STORAGE Sample ture Dry Fluoride FluorideTIME CONDI- Weight Content Weight Reading Conc. POINT TIONS (g) (%) (g)(ppm) (ug/g) T = 0 5-8° C. 0.588 17.5 0.485 0.06 15 20-25° C. 40° C. T =2 5-8° C. 0.501 16.7 0.417 0.05 15 WEEKS 20-25° C. 0.532 16.6 0.444 0.0721 40° C. 0.509 15.8 0.429 0.54 161 T = 4 5-8° C. 0.506 16.1 0.425 0.026 WEEKS 20-25° C. 0.505 15.2 0.428 0.03 9 40° C. 0.523 15.1 0.444 0.613178 T = 6 5-8° C. 0.502 15.62 0.424 0.02 6 WEEKS 20-25° C. 0.501 14.390.429 0.04 12 40° C. 0.517 14.28 0.443 1.11 323 T = 8 5-8° C. 0.51516.32 0.431 0.04 12 WEEKS 20-25° C. 0.512 15.95 0.430 0.04 12 40° C.0.508 14.46 0.435 1.09 324 T = 9 5-8° C. 0.5 16.83 0.416 0.03 9 WEEKS20-25° C. 0.51 15.41 0.431 0.206 62 40° C. 0.503 15.34 0.426 1.43 434 T= 10 5-8° C. 0.506 16.36 0.423 0.04 12 WEEKS 20-25° C. 0.508 15.82 0.4280.22 66 40° C. 0.507 15.2 0.430 1.67 501 T = 12 5-8° C. 0.504 16.360.422 0.26 8 WEEKS 20-25° C. 0.501 15.82 0.422 1.8 55 40° C. 0.508 15.20.431 1.94 581

TABLE 10 Sample 6H Mois- Sample STORAGE Sample ture Dry FluorideFluoride TIME CONDI- Weight Content Weight Reading Conc. POINT TIONS (g)(%) (g) (ppm) (ug/g) T = 0 5-8° C. 0.511 7.82 0.471 0.19 50 20-25° C.40° C. T = 2 5-8° C. 0.510 7.07 0.474 0.17 46 WEEKS 20-25° C. 0.544 7.180.505 0.40 102 40° C. 0.502 8.16 0.461 1.10 308 T = 4 5-8° C. 0.538 7.20.499 0.20 52 WEEKS 20-25° C. 0.508 6.21 0.476 0.38 103 40° C. 0.5017.47 0.464 2.03 565 T = 6 5-8° C. 0.509 6.38 0.477 0.16 44 WEEKS 20-25°C. 0.521 6.91 0.485 0.39 103 40° C. 0.500 7.08 0.465 2.04 566 T = 8 5-8°C. 0.523 7.16 0.486 0.14 37 WEEKS 20-25° C. 0.530 7.31 0.491 0.31 81 40°C. 0.500 7.67 0.462 1.89 528 T = 9 5-8° C. 0.531 7.89 0.489 0.35 92WEEKS 20-25° C. 0.501 7.8 0.462 0.79 221 40° C. 0.518 8.19 0.476 2.41654 T = 10 5-8° C. 0.510 7.89 0.470 0.33 90 WEEKS 20-25° C. 0.516 7.800.476 0.88 239 40° C. 0.501 8.19 0.460 2.58 724 T = 12 5-8° C. 0.5047.89 0.464 2.03 57 WEEKS 20-25° C. 0.502 7.80 0.463 5.75 160 40° C.0.495 8.19 0.454 3.20 908

TABLE 11 Example 6I Mois- Sample STORAGE Sample ture Dry FluorideFluoride TIME CONDI- Weight Content Weight Reading Conc. POINT TIONS (g)(%) (g) (ppm) (ug/g) T = 0 5-8° C. 0.502 16.1 0.421 <0.07 <15 20-25° C.40° C. T = 2 5-8° C. 0.520 16.9 0.432 0.03 9 WEEKS 20-25° C. 0.510 15.80.429 0.06 19 40° C. 0.510 14.5 0.436 0.70 214 T = 4 5-8° C. 0.505 16.20.423 0.04 12 WEEKS 20-25° C. 0.519 14.7 0.443 0.03 9 40° C. 0.507 14.50.433 0.91 280 T = 6 5-8° C. 0.513 16.8 0.427 0.02 7 WEEKS 20-25° C.0.504 14.8 0.429 0.03 9 40° C. 0.554 14.1 0.476 1.09 305 T = 8 5-8° C.0.511 16.09 0.429 0.03 9 WEEKS 20-25° C. 0.505 15.58 0.426 0.03 9 40° C.0.554 14.46 0.474 1.13 317 T = 9 5-8° C. 0.506 16.69 0.422 0.04 12 WEEKS20-25° C. 0.516 15.49 0.436 0.22 67 40° C. 0.526 15.07 0.447 1.75 522 T= 10 5-8° C. 0.509 16.69 0.424 0.04 12 WEEKS 20-25° C. 0.505 15.49 0.4270.23 72 40° C. 0.517 15.07 0.439 1.74 527 T = 12 5-8° C. 0.503 16.690.419 0.314 9 WEEKS 20-25° C. 0.501 15.49 0.423 1.76 56 40° C. 0.51715.07 0.439 2.22 674

TABLE 12 Sample 6J Mois- Sample STORAGE Sample ture Dry FluorideFluoride TIME CONDI- Weight Content Weight Reading Conc. POINT TIONS (g)(%) (g) (ppm) (ug/g) T = 0 5-8° C. 0.563 8.59 0.515 0.13 33 20-25° C.40° C. T = 2 5-8° C. 0.545 7.60 0.504 0.12 32 WEEKS 20-25° C. 0.520 7.350.482 0.25 69 40° C. 0.501 8.21 0.460 0.66 192 T = 4 5-8° C. 0.513 7.220.476 0.11 31 WEEKS 20-25° C. 0.526 7.83 0.485 0.22 60 40° C. 0.516 7.830.476 0.91 254 T = 6 5-8° C. 0.519 7.93 0.478 0.09 25 WEEKS 20-25° C.0.503 8.00 0.463 0.21 60 40° C. 0.511 7.80 0.471 0.94 266 T = 8 5-8° C.0.518 8.16 0.476 0.11 31 WEEKS 20-25° C. 0.532 7.91 0.490 0.22 60 40° C.0.509 8.11 0.468 0.97 276 T = 9 5-8° C. 0.510 9.19 0.463 0.19 55 WEEKS20-25° C. 0.535 8.44 0.490 0.62 168 40° C. 0.511 8.07 0.470 1.86 527 T =10 5-8° C. 0.503 9.19 0.457 0.18 52 WEEKS 20-25° C. 0.511 8.44 0.4680.61 174 40° C. 0.509 8.07 0.468 1.87 533 T = 12 5-8° C. 0.500 9.190.454 1.45 43 WEEKS 20-25° C. 0.510 8.44 0.467 4.57 130 40° C. 0.5188.07 0.476 2.36 660

Example 7: Potassium Binding Capacity of Polyol Stabilized FAA

Materials.

The materials used were potassium chloride (Reagent Plus grade, ≥99%,Sigma #P4504 or equivalent); de-ionized water greater than 18 megaohmresistivity; IC potassium standard (1,000 ppm, Alltech Cat#37025 orequivalent); ion chromatography (IC) potassium standard, 1000 ppm from asecondary source (e.g. Fisher Scientific #CS-K2-2Y); and methanesulfonicacid (MSA, 99.5%; Aldrich #471356). The MSA was used to make the ICmobile phase if the apparatus used was unable to generate the mobilephase electrolytically.

Preparation of 200 mM KCl Solution.

Potassium chloride (14.91 g) was dissolved in 800 mL of water. Agraduated cylinder was used and water was added to make a 1 L solution.This solution was the 200 mM potassium chloride solution for the bindingassay.

QC and Linear Curve Preparation for IC Analysis.

Potassium standard solutions (100, 250, 500 ppm) for IC were prepared bydiluting a stock 1000 ppm solution with distilled (DI) water. The QCcheck standard was obtained by diluting a second source certified 1000ppm potassium standard with DI water to achieve 250 ppm concentration.

Preparation of Sample Solution.

Two samples of Ca(polyFAA) prepared by the method of Example 4 (500 mg)were placed into separate screw top vials. Using the equation below, theamount of 200 mM KCl solution to add to the vial was calculated:

${i.\mspace{14mu} \frac{\frac{M}{100} \times \lbrack {100 - {S \times ( {1 - \frac{W}{100}} )} - W} \rbrack}{20}}\mspace{14mu} ({mL})$

where M is Ca(polyFAA) sample weight (mg), S is sorbitol content basedon dry weight of Ca(polyFAA), and W is loss on drying (%). Thecalculated volume of 200 mM KCl solution was added to each vial using a10 mL pipettor. The vials were capped tightly. Two blank vialscontaining 15 mL of 200 mM KCl solution were prepared. The vials weretumbled on a rotary tumbler for two hours at about 35 rpm. After twohours, the vials were removed from the tumbler. The contents wereallowed to settle for 5 minutes. Each sample (2-10 mL) and a blank werefiltered over a 0.45 micron filter. Each filtered sample was diluted1:20 by adding 500 μL of each sample or blank to 9500 μL of water. Thediluted filtrate was analyzed for potassium content using IC.

Sample Analysis by IC.

If a 20 mM MSA mobile phase could not be generated electrolytically, the20 mM stock MSA mobile phase was made by diluting MSA in water. The IChad the following settings: injection volume: 5 μL; flow rate: 1 mL/min;column temperature: 35° C.; sample compartment temperature: ambient; runtime: 20 min; and CD25 settings: current 88 mA, cell temperature 35° C.,autorange. Each blank and sample was injected twice.

The IC system used was a Dionex IC System 2000 equipped with AS50autosampler, conductivity Detector CD25 and DS3 flow cell. The columnused was a CS12A 250×4 mm ID analytical column, Dionex #016181 coupledwith a CG12A 50×4 mm ID guard column (optional), Dionex#046074. Thesuppressor used was a Dionex CSRS-Ultra II (4 mm) Suppressor,Dionex#061563. The software used for data acquisition was DionexChromeleon Chromatography Software. The eluent cartridge was a Dionex#058902 to generate the methanesulfonic acid (MSA) mobile phaseelectrolytically.

Data Analysis.

The concentration of potassium was reported in mM. The equation belowwas used to calculate the binding capacity of each sample:

Binding capacity(mmol/g)=(c _(Blank) −c _(Sample))

where c_(Blank) is average concentration of potassium in the 20-folddiluted blank by IC analysis (mM), and c_(sample) is averageconcentration of potassium in the 20-fold diluted sample solution by ICanalysis (mM). The average of the duplicates was reported. The deviationof each individual value was a maximum of 10% from the mean. When alarger deviation was obtained, the assay was repeated.

Results.

A Ca(polyFAA) sample prepared by the process described in Example 4 hada potassium binding capacity of 1.60 mmol/g. A similar Ca(polyFAA)sample was slurried with a 20 wt. %, 25 wt. %, 30 wt. %, and a 45 wt. %solution of D-sorbitol using the process described in Example 6. Thepotassium binding capacities for those stabilized Ca(polyFAA) samplesare described in the Table 13.

TABLE 13 Ca(polyFAA) slurried with Potassium Binding Capacity (mmol/g)20 wt. % sorbitol 1.62 25 wt. % sorbitol 1.67 30 wt. % sorbitol 1.61 45wt. % sorbitol 1.63

Example 8: Human Clinical Study Part A:

Methyl 2-fluoroacrylate (MeFA) was purchased and was vacuum distilledbefore use. Divinylbenzene (DVB) was purchased from Aldrich, technicalgrade, 80%, mixture of isomers, and was used as received. 1,7-octadiene(ODE), lauroyl peroxide (LPO), polyvinyl alcohol (PVA) (typicalmolecular weight 85,000-146,000, 87-89% hydrolyzed), sodium chloride(NaCl), sodium phosphate dibasic heptahydrate (Na₂HPO₄ 7H₂O) and sodiumphosphate monobasic monohydrate (NaH₂PO₄H₂O) were purchased fromcommercial sources and used as received.

In an appropriately sized reactor with appropriate stirring and otherequipment, a 90:5:5 weight ratio mixture of organic phase of monomerswas prepared by mixing methyl 2-fluoroacrylate, 1,7-octadiene, anddivinylbenzene. One-half part of lauroyl peroxide was added as aninitiator of the polymerization reaction. A stabilizing aqueous phasewas prepared from water, polyvinyl alcohol, phosphates, sodium chloride,and sodium nitrite. The aqueous and monomer phases were mixed togetherunder nitrogen at atmospheric pressure, while maintaining thetemperature below 30° C. The reaction mixture was gradually heated whilestirring continuously. Once the polymerization reaction has started, thetemperature of the reaction mixture was allowed to rise to a maximum of95° C.

After completion of the polymerization reaction, the reaction mixturewas cooled and the aqueous phase was removed. Water was added, themixture was stirred, and the solid material was isolated by filtration.The solid was then washed with water to yield a crosslinked (methyl2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer. The (methyl2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer was hydrolyzedwith an excess of aqueous sodium hydroxide solution at 90° C. for 24hours to yield (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadienepolymer. After hydrolysis, the solid was filtered and washed with water.The (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer wasexposed at room temperature to an excess of aqueous calcium chloridesolution to yield insoluble cross-linked (calcium2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer.

After the calcium ion exchange, the wet polymer is slurried with 25-30%w/w aqueous solution of sorbitol at ambient temperature to yieldsorbitol-loaded polymer. Excess sorbitol is removed by filtration. Theresulting polymer is dried at 20-30° C. until the desired moisturecontent (10-25 w/w/%) is reached. This provides a sorbitol loaded,cross-linked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadienepolymer.

Part B:

The objective of the study was to evaluate the equivalence of once aday, two times a day and three times a day dosing of the polymer fromPart A of this example. After a four day period to control diet, 12healthy volunteers were randomized in an open-label, multiple-dosecrossover study. The polymer was administered orally as an aqueoussuspension of 30 grams (g) once a day for six days, 15 g twice a day forsix days, and 10 g three times a day for 6 days in a randomly assignedorder based upon 1 of 6 dosing sequences. Laboratory and adverse eventassessments were performed throughout the study to monitor safety andtolerability. Subjects were required to consume a controlled diet forthe duration of the study. Feces and urine were collected over 24 hourintervals on certain study days to assess potassium excretion.

Subjects were healthy adult males or females without a history ofsignificant medical disease, 18 to 55 years of age, with a body massindex between 19 and 29 kg/m² at the screening visit, serum potassiumlevel >4.0 and <5.0 mEq/L, and serum magnesium, calcium, and sodiumlevels within normal range. Females of childbearing potential must havebeen non-pregnant and non-lactating and must have used a highlyeffective form of contraception before, during, and after the study.

Multiple-dose administration of 30 g polymer for 6 days each as either30 g once daily, 15 g twice daily or 10 g three-times daily,respectively was well tolerated. No serious adverse events werereported, and all adverse events were mild or moderate in severity. Aneffect was apparent for fecal and urinary excretion of potassium.

For fecal potassium excretion, the mean daily values and change frombaseline values were significantly increased for all three dosingregimens. The volunteers receiving the polymer once per day excreted82.8% of the amount of fecal potassium as those volunteers who receivedsubstantially the same amount of the same polymer three-times per day.It is also shown that volunteers receiving the polymer twice per dayexcreted 91.5% of the amount of fecal potassium as those volunteers whoreceived substantially the same amount of the same polymer three-timesper day. For urinary potassium excretion, the mean daily values andchange from baseline values were significantly decreased for all threedosing regimens. Surprisingly, there was no statistically significantdifference between the three dosing regimens.

Regarding tolerability, 2 of the 12 subjects receiving once a day dosingor twice a day dosing reported mild or moderate gastrointestinal adverseevents (including flatulence, diarrhea, abdominal pain, constipation,stomatitis, nausea and/or vomiting). Also, 2 of 12 subjects reportedmild or moderate gastrointestinal adverse events on the baseline controldiet. Thus, less than 16.7% of these subjects reported mild or moderategastrointestinal adverse events, an indication that, as used herein,dosing once or twice a day was well tolerated. None of the subjectsreported severe gastrointestinal adverse events for any of the dosingregimens or at baseline.

Part C:

Another study was performed to assess the safety and efficacy of abinding polymer that was the same as described above in Part A of thisexample, but without the sorbitol loading. Thirty-three healthy subjects(26 male and 7 female) between the ages of 18 and 55 years receivedsingle and multiple doses of polymer or placebo in a double-blind,randomized, parallel-group study. Eight subjects each were randomlyassigned to one of four treatment groups receiving polymer or matchingplacebo. The subjects received 1, 5, 10, or 20 g of polymer or placeboas a single dose on study day 1, followed by three times daily dosingfor eight days following seven days of diet control. Subjects wererequired to consume a controlled diet for the duration of the study.

The polymer was well-tolerated by all subjects. No serious adverseevents occurred. Gastrointestinal adverse events reported were mild tomoderate in severity for one subject. There was no apparent doseresponse relationship in gastrointestinal or overall adverse eventreporting, and no increase in adverse event reports versus placebo.

At the end of the multiple-dose study period, a dose response effect wasapparent for fecal and urinary excretion of potassium. For fecalpotassium excretion, the mean daily values and change from baselinevalues were significantly increased in a dose-related manner. Forurinary potassium excretion, the mean daily values and change frombaseline values were decreased in a dose-related manner.

In comparison of Part C to Part B, those volunteers receiving the sameamount of polymer that had the sorbitol loading (Part B) excreted about20% more potassium in the feces as compared to those volunteersreceiving the non-sorbitol loaded polymer (Part C).

When introducing elements of the present invention or the embodiments(s)thereof, the articles “a”, “an”, “the” and “said” are intended to meanthat there are one or more of the elements. The terms “comprising”,“including” and “having” are intended to be inclusive and mean thatthere may be additional elements other than the listed elements.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

As various changes could be made in the above compositions and methodswithout departing from the scope of the invention, it is intended thatall matter contained in the above description shall be interpreted asillustrative and not in a limiting sense.

What is claimed is:
 1. A process for preparing a crosslinked cationexchange polymer salt, the process comprising mixing the crosslinkedcation exchange polymer salt with a solution of a linear sugar alcohol,the crosslinked cation exchange polymer comprising structural unitscorresponding to Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2,and 3, wherein Formula 1, Formula 2, and Formula 3 are represented bythe following structures:

wherein R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, oraryl; A₁ is carboxylic, phosphonic, or phosphoric; X₁ is arylene; and X₂is alkylene, an ether moiety, or an amide moiety.
 2. The process ofclaim 1 wherein the structural units represented by Formulae 1, 2, and 3are represented by the following structures:


3. The process of claim 1 wherein the polymer comprises structural unitscorresponding to Formulae 1, 2 and
 3. 4. The process of claim 1 whereinthe polymer comprises structural units corresponding to Formulae 1 and2.
 5. The process of claim 1 wherein the polymer comprises structuralunits corresponding to Formulae 1 and
 3. 6. The process of claim 1wherein the cation of the salt is calcium, sodium, or a combinationthereof.
 7. The process of claim 1 wherein the cation of the saltcomprises calcium.
 8. The process of claim 1 wherein the linear sugaralcohol is selected from the group consisting of arabitol, erythritol,glycerol, maltitol, mannitol, ribitol, sorbitol, xylitol, threitol,galactitol, isomalt, iditol, lactitol and combinations thereof.
 9. Theprocess of claim 1 wherein the linear sugar alcohol is sorbitol,xylitol, or a combination thereof.
 10. The process of claim 8 whereinthe cation of the salt is calcium, sodium, or a combination thereof. 11.The process of claim 9 wherein the cation of the salt comprises calcium.12. The process of claim 2 wherein the polymer comprises structuralunits corresponding to Formulae 1, 2 and 3, the cation of the saltcomprises calcium and the linear sugar alcohol comprises sorbitol.
 13. Aprocess for preparing a crosslinked cation exchange polymer salt, theprocess comprising mixing the crosslinked cation exchange polymer saltwith a solution of a linear sugar alcohol, the crosslinked cationexchange polymer being a reaction product of a polymerization mixturecomprising monomers of either (i) Formulae 11 and 22, (ii) Formulae 11and 33, or (iii) Formulae 11, 22, and 33, wherein Formula 11, Formula22, and Formula 33 are represented by the following structures:

and wherein R₁ and R₂ are each independently hydrogen, alkyl,cycloalkyl, or aryl; A₁₁ is an optionally protected carboxylic,phosphonic, or phosphoric; X₁ is arylene; and X₂ is alkylene, an ethermoiety, or an amide moiety.
 14. The process of claim 13 wherein A₁₁ is aprotected carboxylic, phosphonic, or phosphoric.
 15. The process ofclaim 13 wherein Formulae 11, 22, and 33 are represented by thefollowing structures:


16. The process of claim 13 wherein the polymer comprises structuralunits corresponding to Formulae 11, 22, and
 33. 17. The process of claim13 wherein the cation of the salt is calcium, sodium, or a combinationthereof.
 18. The process of claim 13 wherein the linear sugar alcohol isselected from the group consisting of arabitol, erythritol, glycerol,maltitol, mannitol, ribitol, sorbitol, xylitol, threitol, galactitol,isomalt, iditol, lactitol and combinations thereof.
 19. The process ofclaim 13 wherein the linear sugar alcohol is sorbitol, xylitol, or acombination thereof.
 20. The process of claim 15 further comprisinghydrolysis of the protected carboxylic acid group, wherein the polymercomprises structural units corresponding to Formulae 11, 22, and 33, thecation of the salt comprises calcium, and the linear sugar alcoholcomprises sorbitol.
 21. A crosslinked cation exchange polymer saltloaded with a stabilizing amount of a linear sugar alcohol, the polymersalt being prepared by the process of claim
 1. 22. A crosslinked cationexchange polymer salt loaded with a stabilizing amount of a linear sugaralcohol, the polymer salt being prepared by the process of claim 13.